Pyrazolo[3,4-b]pyridines and imidazo[1,5-b]pyridazines as PDE1 inhibitors

ABSTRACT

The present invention provides compounds of formula (I) that are PDE1 enzyme inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Danish Application No. PA201600784,filed Dec. 22, 2016, and Danish Application No. PA201700404, filed Jul.6, 2017, the entire contents of which are hereby incorporated herein byreference.

FIELD OF THE INVENTION

The present invention provides compounds that are PDE1 enzyme inhibitorsand their use as medicaments, in particular for the treatment ofneurodegenerative disorders and psychiatric disorders. The presentinvention also provides pharmaceutical compositions comprising compoundsof the invention and methods of treating disorders using the compoundsof the invention.

BACKGROUND OF THE INVENTION

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signalling. The catalytic activities of PDEsprovide for breakdown of cNs over a spectrum of cN-concentrations in allcells, and their varied regulatory mechanisms provide for integrationand crosstalk with myriads of signalling pathways. Particular PDEs aretargeted to discrete compartments within cells where they control cNlevel and sculpt microenvironments for a variety of cN signalosomes(Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca^(2α)-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, PDE1 represents an interesting regulatory link betweencyclic nucleotides and intracellular Ca²⁺. The PDE1 family is encoded bythree genes: PDE1A (mapped on human chromosome 2q32), PDE1B (humanchromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They havealternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain contains two Ca²⁺/CaM bindingdomains and two phosphorylation sites and different splice variants havedifferent variations of the N-terminal domain, which can give proteinswith different amino acid sequence with different biochemical functions.PDE1 is a dual substrate PDE and the PDE1C-subtype has equal activitytowards cAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1Bhave a preference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignalling pathways, preferably in the nervous system and PDE1inhibitors can enhance the levels of the second messenger's cAMP/cGMPleading to modulation of neuronal processes and to the expression ofneuronal plasticity-related genes, neurotrophic factors, andneuroprotective molecules. These neuronal plasticity enhancementproperties together with the modulation of synaptic transmission makePDE1 inhibitors good candidates as therapeutic agents in manyneurological and psychiatric conditions. The evaluation of PDE1inhibitors in animal models (for reviews see e.g. Blokland et al. ExpertOpinion on Therapeutic Patents (2012), 22(4), 349-354; and Medina, A. E.Frontiers in Neuropharmacology (2011), 5(February), 21) has suggestedthe potential for the therapeutic use of PDE1 inhibitors in neurologicaldiseases, like e.g. Alzheimer's, Parkinson's and Huntington's Diseasesand in psychiatric disorders like e.g. Attention Deficit HyperactivityDisorder (ADHD), depression, anxiety, narcolepsy, cognitive impairmentand cognitive impairment associated with schizophrenia (CIAS) and inrestless leg syndrome. There have also been patent applications claimingthat PDE1 inhibitors are useful in diseases that may be alleviated bythe enhancement of progesterone-signalling such as female sexualdysfunction (e.g. WO 2008/070095).

Various chemical structures with PDE1 inhibiting activity have beenidentified. For example, WO 2016/055618 discloses triazolopyrazinones asPDE1 inhibitors; WO 2016/042775, US 2016/0083391 and US 2016/0083400disclose tricyclic lactams as PDE1 inhibitors; WO 2016/147659 and WO2016/170064 discloses imidazotriazinones as PDE1 inhibitors; and WO2016/174188 discloses imidazopyrazinones as PDE1 inhibitors.

Current treatments for neurodegenerative and/or psychiatric disordersare not efficacious in all patients. Hence, there remains a need foralternative methods of treatment of such diseases and for this purposePDE1 inhibitors may be a good alternative. The present inventiondiscloses new pyrazolo[3,4-b]pyridines and imidazo[1,5-b]pyridazineswith PDE1 inhibitor activity and good physicochemical properties as PDE1inhibitors.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and neurodegenerative disorders.

Accordingly, the present invention relates to compounds of formula (I)

-   wherein-   Z1 is selected from NH, CH₂, O and S;-   Z2 is selected from NH, CH₂, O and S;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₄ alkyl and saturated monocyclic C₃₋₄ cycloalkyl,    wherein said linear or branched C₁₋₄ alkyl and saturated monocyclic    C₃₋₄ cycloalkyl can be optionally substituted with one or more    halogen;-   R2 is selected from the group consisting of linear or branched C₁₋₆    alkyl, saturated monocyclic C₃₋₆ cycloalkyl, oxetanyl,    tetrahydrofuranyl and tetrahydropyranyl, all of which can optionally    be substituted with one or more halogen;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen,    or-   R3 is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen,    or-   R4 is a phenyl, which can optionally be substituted with one or more    substituents selected from linear or branched C₁₋₄ alkyl, linear or    branched C₁₋₄ alkoxy and halogen, wherein said linear or branched    C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be optionally    substituted with one or more halogen, or-   R4 is a pyridinone, which can optionally be substituted with one or    more substituents selected from linear or branched C₁₋₄ alkyl,    linear or branched C₁₋₄ alkoxy and halogen, wherein said linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be    optionally substituted with one or more halogen; or-   R4 is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen;-   or a pharmaceutically acceptable salt thereof.

Reference to compounds encompassed by the present invention includes thefree base and pharmaceutically acceptable salts of the compounds, suchas acid addition salts of the compounds, racemic mixtures of thecompounds, or the corresponding enantiomer and/or optical isomer of thecompounds for which this is relevant, and polymorphic and amorphic formsof compounds of the present invention and of pharmaceutically acceptablesalts of said compounds, as well as tautomeric forms the compounds forwhich this is relevant. Furthermore, the compounds of the presentinvention and pharmaceutically acceptable salts thereof may potentiallyexist in unsolvated as well as in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like. Both solvatedand unsolvated forms of the compounds and pharmaceutically acceptablesalts thereof are encompassed by the present invention.

In one embodiment, the invention relates to a compound according toformula (I) or a pharmaceutically acceptable salt thereof for use intherapy.

In one embodiment, the invention relates to a compound according toformula (I) or a pharmaceutically acceptable salt thereof, for use inthe treatment of a neurodegenerative disorder, selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease or for the treatment of a psychiatric disorder such as AttentionDeficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a compound according formula (I) or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarrier and/or excipient.

In one embodiment, the invention relates to a method for the treatmentof a neurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome, which method comprises the administration of a therapeuticallyeffective amount of a compound according to formula (I) or apharmaceutically acceptable salt thereof, to a patient in need thereof.

In one embodiment, the invention relates to the use of a compoundaccording to formula (I) or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of aneurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome.

DEFINITIONS

PDE1 Enzymes:

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms unless otherwise specified.

PDE1 Inhibitors:

In the context of the present invention, a compound is considered to bea PDE1 inhibitor if the amount required to reach the IC50 level of anyof the three PDE1 isoforms is 10 micro molar or less, such as less than9 micro molar, such as 8 micro molar or less, such as 7 micro molar orless, such as 6 micro molar or less, such as 5 micro molar or less, suchas 4 micro molar or less, such as 3 micro molar or less. For preferredcompounds of the invention, the required amount of PDE1 inhibitorrequired to reach the IC50 level is 2 micro molar or less, such as 1micro molar or less, in particular 500 nM or less.

Preferred compounds of the invention exhibit selectivity towards thePDE1B isoform meaning that said compounds are stronger as PDE1Binhibitors than as PDE1A and/or PDE1C inhibitors. In preferredembodiments, said compounds are at least two-fold stronger, three-foldstronger, four-fold stronger, five-fold stronger or ten-fold stronger asPDE1B inhibitors than as PDE1A and/or PDE1C inhibitors. In morepreferred embodiments, said compounds are at least fifteen-fold strongeror twenty-fold stronger as PDE1B inhibitors than as PDE1A and/or PDE1Cinhibitors. In preferred embodiments, the required amount of PDE1inhibitor required to reach the IC50 level of PDE1B is 400 nM or less,such as 300 nM or less, 200 nM or less, 100 nM or less, or 50 nM orless, for example 25 nM or less. Selectivity towards the PDE1B isoformmay prevent potentially unwanted effects associated with PDE1A and/orPDE1C inhibition.

Substituents:

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted itis mono-, di-, or tri-substituted. It is understood that where nosubstituents are indicated for an “optionally substituted” moiety, thenthe position is held by a hydrogen atom.

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine. In a preferable embodiment, “halogen” refers tofluorine.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁₋₄ alkyl” is equivalent to “C₁ to C₄ alkyl”.

The terms “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₅ alkyl” and “C₁₋₆ alkyl”refer to a linear (i.e. unbranched) or branched saturated hydrocarbonhaving 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of such groupsinclude, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, n-hexyl.

The term “C₁₋₄alkoxy” refers to a moiety of the formula —OR′, wherein R′indicates C₁₋₄ alkyl as defined above.

The term saturated monocyclic C₃₋₆ cycloalkyl refers to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. C₃₋₄ cycloalkyl refers tocyclopropyl and cyclobutyl.

The term “5-membered heteroaryl” refers to a 5-membered aromaticmonocyclic ring containing 1 to 4 carbon atoms and one or moreheteroatoms selected from oxygen, nitrogen and sulfur. Examples include,but are not limited to pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl,triazolyl, tetrazolyl, thiazolyl, thiophenyl, isoxazolyl andthiadiazolyl.

The term “6-membered heteroaryl” refers to a 6-membered aromaticmonocyclic ring containing 1 to 5 carbon atoms and one or more nitrogenatoms. Particular mention is made of pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl.

The term “9-membered bicyclic heteroaryl” refers to a moiety consistingof a 6-membered aromatic ring and a 5-membered aromatic ring fusedtogether to give a 9-membered bicyclic aromatic moeity. The 9-memberedbicyclic heteroaryl consists of carbon and one or more heteroatomsselected from oxygen, nitrogen and sulfur. Particular mention is made ofbenzoxazol, imidazo[1,5-a]pyridine and imidazo[1,2-a]pyridine.

Isomeric and Tautomeric Forms

Where compounds of the present invention contain one or more chiralcentres reference to any of the compounds will, unless otherwisespecified, cover the enantiomerically or diastereomerically purecompound as well as mixtures of the enantiomers or diastereomers in anyratio.

When a compound with a chiral centre is denoted with the prefix (−) or(+) it is understood that said compound could be either the S-enantiomeror the R-enantiomer. I.e. a compound with the prefix (−) could be eitherthe S-enantiomer or the R-enantiomer and a compound with the prefix (+)could be either the S-enantiomer or the R-enantiomer. When bothenantiomer the (−) and the (+) compound have been exemplified for acompound it follows that one is the S-enantiomer and the other is theR-enantiomer. It follows that if for example compound Example 47 can bedetermined to be the R-enantiomer, then compound Example 48 will be theS-enantiomer and vice versa.

The absolute stereochemistry for a compound of the invention can bedetermined by X-ray crystallography or vibrational circular dichroism.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

Pharmaceutically Acceptable Salts:

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. When acompound of formula (I) contains a free base, such salts are prepared ina conventional manner by treating a solution or suspension of a freebase of formula (I) with a molar equivalent of a pharmaceuticallyacceptable acid. Representative examples of suitable organic andinorganic acids are described below.

Pharmaceutically acceptable salts in the present context is intended toindicate non-toxic, i.e. physiologically acceptable salts. The termpharmaceutically acceptable salts includes salts formed with inorganicand/or organic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin andsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid and benzenesulfonic acid. Some of the acids listedabove are di- or tri-acids, i.e. acids containing two or three acidichydrogens, such as phosphoric acid, sulphuric acid, fumaric acid andmaleic acid.

Additional examples of useful acids to form pharmaceutically acceptablesalts can be found e.g. in Stahl and Wermuth (Eds) “Handbook ofPharmaceutical salts. Properties, selection, and use”, Wiley-VCH, 2008.

Therapeutically Effective Amount:

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate, arrest, partlyarrest, remove or delay the clinical manifestations of a given diseaseand its complications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

Treatment and Treating:

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting, removing or delaying progressof the clinical manifestation of the disease. The patient to be treatedis preferably a mammal, in particular a human being.

Combinations

In one embodiment of the invention, the compound of formula (I) is foruse as stand-alone treatment as the sole active compound.

In another embodiment of the invention, the compound of formula (I) maybe used in combination with a second compound, wherein said secondcompound is selected from the following: a compound useful in active orpassive Tau immunotherapy, a compound useful in active or passive Aβpeptide immunotherapy, an NMDA receptor antagonist, an acetylcholineesterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist, anantiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abetamonoclonal antibody.

In yet another embodiment of the invention, the compound of formula (I)may be used in combination with a second compound, wherein said secondcompound is a compound that is useful in the treatment of a psychiatricdisorder.

The terms “combined use”, “in combination with” and “a combination of”and the like as used herein in the context of the method of theinvention comprising the combined administration of therapeuticallyeffective amounts of a compound of formula (I), and anotherpharmaceutically active compound, is intended to mean the administrationof a compound of formula (I) simultaneously or sequentially, in anyorder, together with said second compound.

The two compounds may be administered simultaneously or with a time gapbetween the administrations of the two compounds. The two compounds maybe administered either as part of the same pharmaceutical formulation orcomposition, or in separate pharmaceutical formulations or compositions.The two compounds may be administered on the same day or on differentdays. They may be administered by the same route, such for example byoral administration, by depot, by intramuscular injection or intravenousinjection; or by different routes wherein one compound is for exampleadministered orally or placed by depot and the other compound is forexample injected. The two compounds may be administered by the samedosage regime or interval, such as once or twice daily, weekly, ormonthly; or by different dosage regimes for example wherein one isadministered once daily and the other is administered twice daily orweekly or monthly.

In some instances, the patient to be treated may already be in treatmentwith one or more of said second compound when treatment with a compoundof formula (I) is initiated. In other instances, the patient may alreadybe in treatment with a compound of formula (I) when treatment with oneor more of said second compound is initiated. In other instances, thetreatment with a compound of formula (I) and treatment with one or moreof said second compound is initiated at the same time.

Compounds for Combination Treatment

In the context of the invention, compounds to be used in combinationwith a compound of formula (I) in the treatment of a neurodegenerativedisorder, are selected from for example a compound useful in active orpassive Tau immunotherapy, a compound useful in active or passive Aβpeptide immunotherapy, an NMDA receptor antagonist, an acetylcholineesterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist, anantiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abetamonoclonal antibody.

In the context of the invention, compounds to be used in combinationwith a compound of formula (I) in the treatment of a psychiatric and/orcognitive disorder, is a compound with a pharmacological activityselected from one or more of the following mechanisms:antagonist/inverse agonist/negative modulator/partial agonist/inhibitorof one or more of the targets dopamine D1 receptor, dopamine D2receptor, dopamine D3 receptor, phosphodiesterase PDE10, serotonin5-HT2A receptor, serotonin 5-HT6 receptor, and glycine transporterGlyT1; or agonist/positive modulator/partial agonist of one or more ofthe targets KCNQ channels, NMDA receptor, AMPA receptor and nicotinicalpha-7 receptor. Examples of such compounds includes clozapine,risperidone, paliperidone, olanzapine, quetiapine, amisulpride,ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidol,iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,levomepromazine, sulpiride, fluphenazine, zuclopenthixol, flupenthixoland cariprazine.

Administration Routes

Pharmaceutical compositions comprising a compound of the presentinvention either as the sole active compound or in combination a secondcompound defined above, may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical Formulations and Excipients

In the following, the term, “excipient” or “pharmaceutically acceptableexcipient” refers to pharmaceutical excipients including, but notlimited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), such as one of the compoundexamples disclosed in the Experimental Section herein. The presentinvention also provides a process for making a pharmaceuticalcomposition comprising a compound of formula (I). The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable excipients in accordance with conventionaltechniques such as those disclosed in Remington, “The Science andPractice of Pharmacy”, 22^(th) edition (2012), Edited by Allen, Loyd V.,Jr.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tabletsor hard or soft capsules), each containing a predetermined amount of theactive ingredient, and preferably one or more suitable excipients. Whereappropriate, the solid dosage forms may be prepared with coatings suchas enteric coatings or they may be formulated so as to provide modifiedrelease of the active ingredient such as delayed or extended releaseaccording to methods well known in the art. Where appropriate, the soliddosage form may be a dosage form disintegrating in the saliva, such asfor example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose. If solid material isused for oral administration, the formulation may for example beprepared by mixing the active ingredient with solid excipients andsubsequently compressing the mixture in a conventional tabletingmachine; or the formulation may for example be placed in a hard capsulee.g. in powder, pellet or mini tablet form. The amount of solidexcipient will vary widely but will typically range from about 25 mg toabout 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol,poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

Doses:

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age, the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have identified compounds that are PDE1inhibitors, and as such are useful to treat neurodegenerative andpsychiatric disorders. The present invention thus provides compounds offormula (I) that are effective in inhibiting PDE1 for use as amedicament in the treatment of a mammal, preferably a human.

The invention provides a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, as well as a pharmaceutical compositioncontaining such a compound, for use in the treatment of a brain diseasewhich could be a neurodegenerative disorder or a psychiatric disorder.In a preferred embodiment, the neurodegenerative disorder is selectedfrom the group consisting of Alzheimer's Disease, Parkinson's Diseaseand Huntington's Disease. In another preferred embodiment, thepsychiatric disorder is selected from the group consisting of AttentionDeficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS). Other brain disorders could be e.g. restless legsyndrome.

This invention further provides a method of treating a brain diseasewhich could be a neurodegenerative or a psychiatric disorder, whichmethod comprises administering to said mammal a pharmaceuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. Examples of neurodegenerative disorders thatcan be treated according to the present invention include Alzheimer'sDisease, Parkinson's Disease and Huntington's Disease, which methodcomprises administering to the subject a therapeutically effectiveamount of a compound of formula (I). Examples of psychiatric disordersthat can be treated according to the present invention include AttentionDeficit Hyperactivity Disorder (ADHD), depression, narcolepsy, cognitiveimpairment and cognitive impairment associated with schizophrenia(CIAS). Other brain disorders to be treated could be e.g. restless legsyndrome.

EMBODIMENTS OF THE INVENTION

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth

-   E1. A compound of formula (I)

-   wherein-   Y1=N—R1, Y2=C and Y3=C, or-   Y1=C—R1, Y2=N and Y3=C;-   Z1 is selected from NH, CH₂, O and S;-   Z2 is selected from NH, CH₂, O and S;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₄ alkyl and saturated monocyclic C₃₋₄ cycloalkyl,    wherein said linear or branched C₁₋₄ alkyl and saturated monocyclic    C₃₋₄ cycloalkyl can be optionally substituted with one or more    halogen;-   R2 is selected from the group consisting of linear or branched C₁₋₆    alkyl, saturated monocyclic C₃₋₆ cycloalkyl, oxetanyl,    tetrahydrofuranyl and tetrahydropyranyl, all of which can optionally    be substituted with one or more halogen;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen,    or-   R3 is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen,    or-   R4 is a phenyl, which can optionally be substituted with one or more    substituents selected from linear or branched C₁₋₄ alkyl, linear or    branched C₁₋₄ alkoxy and halogen, wherein said linear or branched    C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be optionally    substituted with one or more halogen, or-   R4 is a pyridinone, which can optionally be substituted with one or    more substituents selected from linear or branched C₁₋₄ alkyl,    linear or branched C₁₋₄ alkoxy and halogen, wherein said linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be    optionally substituted with one or more halogen; or-   R4 is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen;    or a pharmaceutically acceptable salt thereof.-   E2. The compound according to embodiment 1 of formula (I)

-   wherein-   Y1=N—R1, Y2=C and Y3=C, or-   Y1=C—R1, Y2=N and Y3=C;-   Z1 is selected from NH, CH₂, O and S;-   Z2 is selected from NH, CH₂, O and S;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁-C₄ alkyl and saturated monocyclic C₃-C₄ cycloalkyl,    wherein said linear or branched C₁-C₄ alkyl and saturated monocyclic    C₃-C₄ cycloalkyl can be optionally substituted with one or more    halogen;-   R2 is selected from the group consisting of linear or branched C₁-C₆    alkyl, saturated monocyclic C₃-C₆ cycloalkyl, oxetanyl,    tetrahydrofuranyl and tetrahydropyranyl, all of which can optionally    be substituted with one or more halogen;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁-C₄ alkyl, linear or branched C₁-C₄ alkoxy and halogen,    wherein said linear or branched C₁-C₄ alkyl and linear or branched    C₁-C₄ alkoxy can be optionally substituted with one or more halogen;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁-C₄ alkyl, linear or branched C₁-C₄alkoxy and halogen,    wherein said linear or branched C₁-C₄ alkyl and linear or branched    C₁-C₄alkoxy can be optionally substituted with one or more halogen,    or-   R4 is a phenyl, which can optionally be substituted with one or more    substituents selected from linear or branched C₁-C₄ alkyl, linear or    branched C₁-C₄alkoxy and halogen, wherein said linear or branched    C₁-C₄ alkyl and linear or branched C₁-C₄alkoxy can be optionally    substituted with one or more halogen, or-   R4 is a pyridinone, which can optionally be substituted with one or    more substituents selected from linear or branched C₁-C₄ alkyl,    linear or branched C₁-C₄alkoxy and halogen, wherein said linear or    branched C₁-C₄ alkyl and linear or branched C₁-C₄alkoxy can be    optionally substituted with one or more halogen;-   or a pharmaceutically acceptable salt thereof.-   E3. The compound according to embodiment 1 of formula (I)

-   wherein-   Y1=N—R1, Y2=C and Y3=C, or-   Y1=C—R1, Y2=N and Y3=C;-   Z1 is selected from NH and CH₂;-   Z2 is selected from NH and CH₂;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₄ alkyl and saturated monocyclic C₃₋₄ cycloalkyl,    wherein said linear or branched C₁₋₄ alkyl and saturated monocyclic    C₃₋₄ cycloalkyl can be optionally substituted with one or more    halogen;-   R2 is selected from the group consisting of linear or branched C₁₋₆    alkyl, saturated monocyclic C₃₋₆ cycloalkyl, oxetanyl,    tetrahydrofuranyl and tetrahydropyranyl, all of which can optionally    be substituted with one or more halogen;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen,    wherein said linear or branched C₁₋₄ alkyl and linear or branched    C₁₋₄ alkoxy can be optionally substituted with one or more halogen,    or-   R4 is a phenyl, which can optionally be substituted with one or more    substituents selected from linear or branched C₁₋₄ alkyl, linear or    branched C₁₋₄ alkoxy and halogen, wherein said linear or branched    C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be optionally    substituted with one or more halogen, or-   R4 is a pyridinone, which can optionally be substituted with one or    more substituents selected from linear or branched C₁₋₄ alkyl,    linear or branched C₁₋₄ alkoxy and halogen, wherein said linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be    optionally substituted with one or more halogen;-   or a pharmaceutically acceptable salt thereof.-   E4. The compound according to embodiment 1 of formula (I)

-   wherein-   Y1=N—R1, Y2=C and Y3=C, or-   Y1=C—R1, Y2=N and Y3=C;-   Z1 is selected from NH and CH₂;-   Z2 is selected from NH and CH₂;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is hydrogen or a linear or branched C₁₋₄ alkyl, wherein said    linear or branched C₁₋₄ alkyl can be optionally mono-di- or    tri-substituted with fluorine;-   R2 a linear or branched C₁₋₄ alkyl, wherein said linear or branched    C₁₋₄ alkyl can be optionally mono-di- or tri-substituted with    fluorine;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy; wherein said    linear or branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can    be optionally mono-di- or tri-substituted with fluorine;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy wherein said    linear or branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can    be optionally mono-di- or tri-substituted with fluorine, or-   R4 is a phenyl, which can optionally be substituted with one or more    substituents selected from linear or branched C₁₋₄ alkyl and linear    or branched C₁₋₄alkoxy wherein said linear or branched C₁₋₄ alkyl    and linear or branched C₁₋₄ alkoxy can be optionally mono-di- or    tri-substituted with fluorine, or-   R4 is a pyridinone, which can optionally be substituted with one or    more substituents selected from linear or branched C₁₋₄ alkyl and    linear or branched C₁₋₄ alkoxy wherein said linear or branched C₁₋₄    alkyl and linear or branched C₁₋₄ alkoxy can be optionally mono-di-    or tri-substituted with fluorine;-   or a pharmaceutically acceptable salt thereof.-   E5. The compound according to embodiment 1 of formula (I)

-   wherein-   Y1=N—R1, Y2=C and Y3=C, or-   Y1=C—R1, Y2=N and Y3=C;-   Z1 is selected from NH and CH₂;-   Z2 is selected from NH and CH₂;-   with the proviso that at least one of Z1 and Z2 is CH₂;-   R1 is hydrogen or a linear or branched C₁₋₄ alkyl;-   R2 is a linear or branched C₁₋₆ alkyl;-   R3 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy;-   R4 is a 5- or 6-membered heteroaryl, which can optionally be    substituted with one or more substituents selected from linear or    branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy;-   or a pharmaceutically acceptable salt thereof.-   E6. The compound according to any of embodiments 1, 2, 3 or 4 of    formula (Ia)

-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 1, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 2, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 3, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 4; or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 5;-   or a pharmaceutically acceptable salt thereof.-   E7. The compound according to any of embodiments 1, 2, 3 or 4 of    formula (Ib)

-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 1, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 2, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 3, or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 4; or-   wherein Z1, Z2, R1, R2, R3 and R4 are as defined in embodiment 5;

or a pharmaceutically acceptable salt thereof.

-   E8. The compound according to any of embodiments 1-7, wherein the    term “halogen” indicates fluorine.-   E9. The compound according to any of embodiments 1-8, wherein Z1 is    NH.-   E10. The compound according to any of embodiments 1-9, wherein Z2 is    CH₂.-   E11. The compound according to any of embodiments 1-10, wherein Z1    is NH and Z2 is CH₂.-   E12. The compound according to any of embodiments 1-11, wherein R1    is linear or branched C₁₋₄ alkyl.-   E13. The compound according to embodiment 12, wherein R1 is methyl.-   E14. The compound according to any of embodiments 1-13, wherein R2    is linear or branched C₁₋₆ alkyl.-   E15. The compound according to embodiment 14, wherein R2 is selected    from isopropyl and 1-methyl-propyl.-   E16. The compound according to any of embodiments 1-15, wherein R3    is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl,    oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and    thiophenyl, all of which can optionally be substituted with a    methyl.-   E17. The compound according to embodiment 16, wherein R3 is a    5-membered heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl,    oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and thiophenyl,    wherein said 5-membered heteroaryl is substituted with a methyl.-   E18. The compound according to any of embodiments 1-15, wherein R3    is a 6-membered heteroaryl, which can optionally be substituted with    a substituent selected from methyl, trifluoromethyl and linear or    branched C₁₋₄ alkoxy.-   E19. The compound according to embodiment 18, wherein said    6-membered heteroaryl is selected from pyridyl, pyrimidinyl,    pyrazinyl and pyridazinyl.-   E20. The compound according to any of embodiments 1-15, wherein R3    is pyridyl, which is substituted with a linear or branched C₁₋₄    alkoxy.-   E21. The compound according to any of embodiments 1-15, wherein R3    is a 9-membered bicyclic heteroaryl, which is optionally substituted    with one or more methyl.-   E22. The compound according to embodiment 21, wherein said    9-membered bicyclic heteroaryl is selected from benzoxazol,    imidazo[1,5-a]pyridine and imidazo[1,2-a]pyridine.-   E23. The compound according to any of embodiments 1-21, wherein R4    is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl,    oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and    thiophenyl, all of which can optionally be substituted with a    methyl.-   E24. The compound according to embodiment 23, wherein R4 is a    5-membered heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl,    oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and thiophenyl,    wherein said 5-membered heteroaryl is substituted with a methyl.-   E25. The compound according to any of embodiments 1-22, wherein R4    is a 6-membered heteroaryl, which can optionally be substituted with    a linear or branched C₁₋₄ alkoxy.-   E26. The compound according to embodiment 25, wherein said    6-membered heteroaryl is selected from pyridyl, pyrimidinyl,    pyrazinyl and pyridazinyl.-   E27. The compound according to any of embodiments 1-23, wherein R4    is a pyridyl, which is substituted with a linear or branched C₁₋₄    alkoxy.-   E28. The compound according to any of embodiments 1-23, wherein R4    is 2-ethoxy-3-pyridyl.-   E29. The compound according to any of embodiments 1-23, wherein R4    is a phenyl, which can optionally be substituted with one or more    methyl.-   E30. The compound according to any of embodiments 1-23, wherein R4    is a pyridinone, which can optionally be substituted with one or    more methyl.-   E31. The compound according to any of embodiments 1-23, wherein R4    is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more methyl.-   E32. The compound according to embodiment 31, wherein said    9-membered bicyclic heteroaryl is selected from benzoxazol,    imidazo[1,5-a]pyridine and imidazo[1,2-a]pyridine.-   E33. The compound according to any of embodiments 1-15, wherein-   R3 is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl,    oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and    thiophenyl, all of which can optionally be substituted with a    methyl; or-   R3 is a 6-membered heteroaryl, which can optionally be substituted    with a substituent selected from methyl, trifluoromethyl or a linear    or branched C₁₋₄ alkoxy; wherein said 6-membered heteroaryl is    selected from pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl,    triazolyl, tetrazolyl, thiazolyl and thiophenyl; or-   R3 is a 9-membered bicyclic heteroaryl, which is optionally    substituted with one or more methyl.-   E34. The compound according to any of embodiments 1-15, wherein-   R4 is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl,    oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and    thiophenyl wherein said 5-membered heteroaryl can be optionally    substituted with a methyl; or-   R4 is a 6-membered heteroaryl, which can optionally be substituted    with a linear or branched C₁₋₄ alkoxy; wherein said 6-membered    heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl and    pyridazinyl; or-   R4 is a phenyl, which can optionally be substituted with one or more    methyl; or-   R4 is a pyridinone, which can optionally be substituted with one or    more methyl; or-   R4 is a 9-membered bicyclic heteroaryl, which can optionally be    substituted with one or more methyl.-   E35. The compound according to embodiment 1, wherein the compound is    selected from the group consisting of:    -   1.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine    -   2.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   3.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;    -   4.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   5.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   6.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   7.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;    -   8.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylimidazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   9.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   10.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;    -   11.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   12.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   13.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   14.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   15.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   16.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   17.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methylthiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   18.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-4-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;    -   19.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   20.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   21.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   22.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   23.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltetrazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   24.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   25.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;    -   26.        6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine;    -   27.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   28.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   29.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   30.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;    -   31.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   32.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   33.        3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;    -   34.        3-isopropyl-1-methyl-N-[(1-methylimidazol-4-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;    -   35.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   36.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;    -   37.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;    -   38.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   39.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;    -   40.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(2-pyridylmethyl)pyrazolo[3,4-b]pyridin-4-amine;    -   41.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;    -   42.        6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   43.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;    -   44.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltriazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   45.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   46.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   47.        (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine; 48.        (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   49.        (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   50.        (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   51.        (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   52.        (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   53.        (+)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   54.        (−)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;    -   55.        3-isopropyl-6-(2-methoxy-3-pyridyl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   56.        3-(3-isopropyl-1-methyl-4-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-methylpyridin-2(1H)-one;    -   57.        3-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine;    -   58.        3-isopropyl-1-methyl-6-(2-methyl-3-thienyl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   59.        3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl-1H-pyrazolo[3,4-b]pyridin-4-amine;    -   60.        3-isopropyl-1-methyl-6-(4-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   61.        3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl-1H-pyrazolo[3,4-b]pyridin-4-amine;    -   62.        3-isopropyl-1-methyl-6-(5-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   63.        3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-phenyl-pyrazolo[3,4-b]pyridin-4-amine;    -   64.        3-isopropyl-6-(4-methoxypyrimidin-5-yl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   65.        3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-thienyl)pyrazolo[3,4-b]pyridin-4-amine;    -   66.        6-(3-ethoxypyridazin-4-yl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   67.        3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(3-propoxypyridazin-4-yl)pyrazolo[3,4-b]pyridin-4-amine;    -   68.        6-(3-ethoxy-4-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;    -   69.        2-(3-ethoxypyridazin-4-yl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   70.        2-(3-ethoxy-4-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;    -   71.        5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;    -   72.        5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;    -   73.        2-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   74.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(2-pyridylmethyl)imidazo[1,5-b]pyridazin-4-amine;    -   75.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(pyrimidin-2-ylmethy)imidazo[1,5-b]pyridazin-4-amine;    -   76.        2-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   77.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   78.        2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   79.        2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;    -   80.        2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,5-b]pyridazin-4-amine;    -   81.        2-(1,3-benzoxazol-7-yl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;-   or a pharmaceutically acceptable salt of any of these compounds.-   E36. A compound of any one of embodiments 1-35 or a pharmaceutically    acceptable salt thereof, wherein said compound has a PDE1A, PDE1B or    PDE1C IC₅₀ value, determined as described in the section “PDE1    inhibition assay”, of 10 micro molar or less, such as 5 micro molar    or less, such as 4 micro molar or less, such as 3 micro molar or    less, such as 2 micro molar or less, such as 1 micro molar or less,    such as 500 nM or less, such as 400 nM or less, such as 300 nM or    less, such as 200 nM or less, such as 100 nM or less.-   E37. A compound of any one of embodiments 1-35 or a pharmaceutically    acceptable salt thereof, wherein said compound has at least two-fold    lower PDE1B IC₅₀ value, three-fold lower PDE1B IC₅₀ value, four-fold    lower or five-fold lower PDE1B IC₅₀ value than PDE1A IC₅₀ value    and/or PDE1C IC₅₀ value.-   E38. A compound of any one of embodiments 1-37 or a pharmaceutically    acceptable salt thereof, for use in therapy.-   E39. A compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, for use as a medicament.-   E40. A pharmaceutical composition comprising a therapeutically    effective amount of a compound of any one of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, and one or more    pharmaceutically acceptable carriers, diluents and/or excipients.-   E41. The pharmaceutical composition according to embodiment 40 for    use in the treatment of a neurodegenerative disorder, selected from    the group consisting of Alzheimer's Disease, Parkinson's Disease and    Huntington's Disease or for the treatment of a psychiatric disorder    such as Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), or another brain disease like    restless leg syndrome.-   E42. The pharmaceutical composition according to embodiment 40,    wherein said pharmaceutical composition further comprises a second    compound, which compound is selected from a compound useful in    active or passive Tau immunotherapy, a compound useful in active or    passive Aβ peptide immunotherapy, an NMDA receptor antagonist, an    acetylcholine esterase inhibitor, a BACE inhibitor, a 5-HT6 receptor    antagonist, an antiepileptic, an anti-inflammatory drug or an    anti-N3-pGlu Abeta monoclonal antibody.-   E43. The pharmaceutical composition according to embodiment 42,    wherein said composition is for use in the treatment of a    neurodegenerative disorder selected from the group consisting of    Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.-   E44. The pharmaceutical composition according to embodiment 40,    further comprising a second compound, which compound is useful in    the treatment of a psychiatric disorder.-   E45. The pharmaceutical composition according to embodiment 44,    wherein said second compound has a pharmacological activity selected    from one or more of the following mechanisms: antagonist/inverse    agonist/negative modulator/partial agonist/inhibitor of one or more    of the targets dopamine D1 receptor, dopamine D2 receptor, dopamine    D3 receptor, phosphodiesterase PDE10, serotonin 5-HT2A receptor,    serotonin 5-HT6 receptor, and glycine transporter GlyT1; or    agonist/positive modulator/partial agonist of one or more of the    targets KCNQ channels, NMDA receptor, AMPA receptor and nicotinic    alpha-7 receptor.-   E46. The pharmaceutical composition according to embodiment 44,    wherein said second compound is selected from the list comprising    clozapine, risperidone, paliperidone, olanzapine, quetiapine,    amisulpride, ziprasidone, aripiprazole, brexpiprazole, asenapine,    haloperidol, iloperidone, lurasidone, chlorpromazine, blonanserin,    perphenazine, levomepromazine, sulpiride, fluphenazine,    zuclopenthixol, flupenthixol and cariprazine.-   E47. The pharmaceutical composition according to any of embodiments    44-46, wherein said composition is for use in the treatment of a    psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS).-   E48. A compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, for use in the treatment    of a neurodegenerative disorder, selected from the group consisting    of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease    or for the treatment of a psychiatric disorder such as Attention    Deficit Hyperactivity Disorder (ADHD), depression, anxiety,    narcolepsy, cognitive impairment and cognitive impairment associated    with schizophrenia (CIAS), or another brain disease like restless    leg syndrome.-   E49. The compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, for the use in the    treatment of a neurodegenerative disorder selected from the group    consisting of Alzheimer's Disease, Parkinson's Disease and    Huntington's Disease, wherein said compound is used in combination    with a second compound, which compound is selected from a compound    useful in active or passive Tau immunotherapy, a compound useful in    active or passive Aβ peptide immunotherapy, an NMDA receptor    antagonist, an acetylcholine esterase inhibitor, a BACE inhibitor, a    5-HT6 receptor antagonist, an antiepileptic, an anti-inflammatory    drug or an anti-N3-pGlu Abeta monoclonal antibody.-   E50. The compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, for the use in the    treatment of a psychiatric disorder such as Attention Deficit    Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,    cognitive impairment and cognitive impairment associated with    schizophrenia (CIAS), wherein said compound is used in combination    with a second compound, which compound is useful in the treatment of    a psychiatric disorder.-   E51. The compound or pharmaceutically acceptable salt thereof for    the use according to embodiment 50, wherein said second compound,    which compound is useful in the treatment of a psychiatric disorder,    has a pharmacological activity selected from one or more of the    following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E52. The compound or pharmaceutically acceptable salt thereof for    the use according to embodiment 50, wherein said second compound,    which compound is useful in the treatment of a psychiatric disorder,    is selected from the list comprising clozapine, risperidone,    paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone,    aripiprazole, brexpiprazole, asenapine, haloperidol, iloperidone,    lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.-   E53. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome, which    method comprises the administration of a therapeutically effective    amount of a compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, to a patient in need    thereof.-   E54. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease, which method comprises    the administration of a therapeutically effective amount of a    compound according to any of embodiments 1-37 or a pharmaceutically    acceptable salt thereof, in combination with a therapeutically    effective amount of a second compound, which compound is selected    from a compound useful in active or passive Tau immunotherapy, a    compound useful in active or passive Aβ P peptide immunotherapy, an    NMDA receptor antagonist, an acetylcholine esterase inhibitor, a    BACE inhibitor, a 5-HT6 receptor antagonist, an antiepileptic, an    anti-inflammatory drug or an anti-N3-pGlu Abeta monoclonal antibody;    to a patient in need thereof.-   E55. A method for the treatment of a psychiatric disorder such as    Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), which method comprises the    administration of a therapeutically effective amount of a compound    according to any of embodiments 1-37 or a pharmaceutically    acceptable salt thereof, in combination with a therapeutically    effective amount of a second compound, which compound is useful in    the treatment of a psychiatric disorder; to a patient in need    thereof.-   E56. The method according to embodiment 55, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, has a pharmacological activity selected from one or more    of the following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E57. The method according to embodiment 55, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, is selected from the list comprising clozapine,    risperidone, paliperidone, olanzapine, quetiapine, amisulpride,    ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidol,    iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.-   E58. Use of a compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome.-   E59. Use of a compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease, wherein said    medicament is for use in combination with a second compound, which    compound is selected from a compound useful in active or passive Tau    immunotherapy, a compound useful in active or passive Aβ peptide    immunotherapy, an NMDA receptor antagonist, an acetylcholine    esterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist,    an antiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abeta    monoclonal antibody.-   E60. Use of a compound according to any of embodiments 1-37 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a psychiatric disorder such as    Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), wherein said medicament is for    use in combination with a second compound, which compound is useful    in the treatment of a psychiatric disorder.-   E61. The use according to embodiment 60, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, has a pharmacological activity selected from one or more    of the following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E62. The use according to embodiment 61, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, is selected from the list comprising clozapine,    risperidone, paliperidone, olanzapine, quetiapine, amisulpride,    ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidol,    iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way. The use ofany and all examples, or exemplary language (including “for instance”,“for example”, “e.g.”, and “as such”) in the present specification isintended merely to better illuminate the invention, and does not pose alimitation on the scope of invention unless otherwise indicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

Compounds of the Invention

TABLE 1 Compounds of the invention PDE1A, PDE1B, PDE1C, IC₅₀ IC₅₀ IC₅₀Example Compound (nM) (nM) (nM) 16-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1- 7.2 0.71 12methylimidazol-4-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 26-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2- 81 15 99methyloxazol-4-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 36-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N- 56 4.3 58(1H-pyrazol-3-ylmethyl)pyrazolo[3,4-b]pyridin-4- amine 46-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1- 11 0.34 13methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 56-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5- 8.9 1.1 19methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 66-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5- 14 1.2 20methyl-1H-pyrazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 76-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(2-methoxy- 14 2.6 184-pyridyl)methyl]-1-methyl-pyrazolo[3,4- b]pyridin-4-amine 82-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1- 2.4 0.22 2.6methylimidazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 92-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2- 30 4.3 29methyloxazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 102-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N- 15 1.6 13(1H-pyrazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4- amine 112-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1- 2 0.28 2.6methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 122-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5- 3.6 0.35 4methyl-1,2,4-oxadiazol-3-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 132-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5- 4.1 0.31 2.7methyl-1H-pyrazol-3-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 142-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(5-methoxy- 6.2 1.5 5.13-pyridyl)methyl]-7-methyl-imidazo[1,5- b]pyridazin-4-amine 152-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy- 7.3 1.7 94-pyridyl)methyl]-7-methyl-imidazo[1,5- b]pyridazin-4-amine 162-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2- 19 2.8 16methyloxazol-5-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 172-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2- 6.1 1.5 5.7methylthiazol-5-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 182-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N- 33 5.7 16(1H-pyrazol-4-ylmethyl)imidazo[1,5-b]pyridazin-4- amine 196-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1- 44 5.8 56methylpyrazol-4-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 206-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2- 16 2.8 30methyltetrazol-5-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 216-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1- 30 5.3 36methylpyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 222-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1- 17 1.8 16methylpyrazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 232-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2- 5.4 0.77 4.7methyltetrazol-5-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 242-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1- 14 1.8 13methylpyrazol-3-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 256-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(5-methoxy- 16 6.3 183-pyridyl)methyl]-1-methyl-pyrazolo[3,4- b]pyridin-4-amine 266-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N- 110 18 75((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine 276-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2- 53 10 60methyloxazol-5-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 286-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2- 14 4.4 13methylthiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 296-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1- 18 1.6 33methyltriazol-4-yl)methyl]pyrazolo[3,4-b]pyridin- 4-amine 306-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N- 85 16 76(1H-pyrazol-4-ylmethyl)pyrazolo[3,4-b]pyridin-4- amine 316-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5- 110 16 110methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 326-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(3- 82 7.8 63methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 333-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3- 3.4 0.42 5.2yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4- b]pyridin-4-amine 343-isopropyl-1-methyl-N-[(1-methylimidazol-4- 2.7 0.29 3.8yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4- b]pyridin-4-amine 356-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(4- 200 25 180methylpyrimidin-2-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 366-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N- 50 4 77(pyrimidin-2-ylmethyl)pyrazolo[3,4-b]pyridin-4- amine 376-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy- 120 27 463-pyridyl)methyl]-1-methyl-pyrazolo[3,4- b]pyridin-4-amine 386-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[[2- 180 33 180(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[3,4- b]pyridin-4-amine 396-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxy- 27 3.4 252-pyridyl)methyl]-1-methyl-pyrazolo[3,4- b]pyridin-4-amine 406-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(2- 68 8.9 82pyridylmethyl)pyrazolo[3,4-b]pyridin-4-amine 416-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy- 440 110 5602-pyridyl)methyl]-1-methyl-pyrazolo[3,4- b]pyridin-4-amine 426-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(6- 180 20 200methyl-2-pyridyl)methyl]pyrazolo[3,4-b]pyridin-4- amine 432-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N- 40 5.8 34(1,2,4-oxadiazol-3-ylmethyl)imidazo[1,5- b]pyridazin-4-amine 442-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2- 38 5.1 24methyltriazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 452-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5- 42 7.8 37methyl-1,3,4-oxadiazol-2-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 462-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(3- 21 4.1 14methyl-1,2,4-oxadiazol-5-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 47(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1- 44 7.5 32methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 48(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1- 5.8 0.64 4.9methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 49(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl- 14 1.4 7.61,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 50(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl- 5.6 0.53 2.41,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 51(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H- 57 4.3 31pyrazol-3-ylmethyl)-5-[1- methylpropyl]imidazo[1,5-b]pyridazin-4-amine52 (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol- 12 0.65 6.13-ylmethyl)-5-[1-methylpropyl]imidazo[1,5- b]pyridazin-4-amine 53(+)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4- 62 12 11pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 54(−)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4- 9.6 1.8 4.4pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine 553-isopropyl-6-(2-methoxy-3-pyridyl)-1-methyl-N- 130 30 45[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 563-(3-isopropyl-1-methyl-4-(((1-methyl-1H-1,2,4- 290 52 480triazol-3-yl)methyl)amino)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-methylpyridin-2(1H)-one 573-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl- 91 22 6.5N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine 583-isopropyl-1-methyl-6-(2-methyl-3-thienyl)-N- 29 4.6 31[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 593-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4- 99 14 67triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine 603-isopropyl-1-methyl-6-(4-methylthiazol-2-yl)-N- 48 8.8 74[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 613-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4- 32 4.6 46triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine 623-isopropyl-1-methyl-6-(5-methylthiazol-2-yl)-N- 280 170 150[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 633-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3- 83 21 36yl)methyl]-6-phenyl-pyrazolo[3,4-b]pyridin-4- amine 643-isopropyl-6-(4-methoxypyrimidin-5-yl)-1- 66 13 2.9methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine 653-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3- 31 5.1 46yl)methyl]-6-(2-thienyl)pyrazolo[3,4-b]pyridin-4- amine 666-(3-ethoxypyridazin-4-yl)-3-isopropyl-1-methyl- 27 3.7 39N-[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[3,4-b]pyridin-4-amine67 3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3- 7.8 2.7 19yl)methyl]-6-(3-propoxypyridazin-4- yl)pyrazolo[3,4-b]pyridin-4-amine 686-(3-ethoxy-4-pyridyl)-3-isopropyl-1-methyl-N-[(1- 58 5.5 59methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4- b]pyridin-4-amine 692-(3-ethoxypyridazin-4-yl)-5-isopropyl-7-methyl- 24 5.2 25N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 702-(3-ethoxy-4-pyridyl)-5-isopropyl-7-methyl-N-[(1- 21 6.3 28methylpyrazol-4-yl)methyl]imidazo[1,5- b]pyridazin-4-amine 715-isopropyl-7-methyl-N-[(1-methylpyrazol-4- 3.3 1 7yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5- b]pyridazin-4-amine 725-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3- 1.4 0.27 1.1yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5- b]pyridazin-4-amine 732-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3- 33 3.6 29pyridyl)methyl]-5-isopropyl-7-methyl- imidazo[1,5-b]pyridazin-4-amine 742-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(2- 180 27 190pyridylmethyl)imidazo[1,5-b]pyridazin-4-amine 752-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N- 11 0.13 24(pyrimidin-2-ylmethyl)imidazo[1,5-b]pyridazin-4- amine 762-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2- 89 17 110yl)methyl]-5-isopropyl-7-methyl-imidazo[1,5- b]pyridazin-4-amine 772-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy- 48 9 483-pyridyl)methyl]-7-methyl-imidazo[1,5- b]pyridazin-4-amine 782-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-5- 61 5.5 39ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5- b]pyridazin-4-amine 792-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-5- 35 28 19ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5- b]pyridazin-4-amine 802-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[[2- 74 15 72(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,5- b]pyridazin-4-amine 812-(1,3-benzoxazol-7-yl)-5-isopropyl-7-methyl-N- 3.8 0.29 2.5[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5- b]pyridazin-4-amine

Table 1 lists the IC₅₀ values for inhibition of PDE1 by the compounds ofthe invention. The IC₅₀ value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration. The PDE1 assay is described in theExperimental Section.

Experimental Section

Preparation of the Compounds of the Invention—General Methods

The compounds of formula (I) may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethods described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XIII” (published withWiley-Interscience, ISSN: 1934-4783). Preferred methods include, but arenot limited to, those described below.

The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Method 1:

where R₁, R₂, R₃ and R₄ are as described for formula (I); formula Ia isformula (I) with Y1=N−R1, Y2=C and Y3=C; R is an alkyl group such asmethyl or ethyl, M is a metal, a boronic acid moiety or a boronic acidester moiety, and X is a halogen such as chlorine or bromine. Compoundsof general formula IV (Scheme 1) can be prepared by the reaction ofcompounds of general formulae II and III in the presence of an acid suchas acetic acid. Reaction of compounds of general formula IV withhydrazines of general formula V gives compounds of general formula VI.Reaction of compounds of general formulae VI and VII in the presence ofa base such as sodium ethoxide followed by a ring-closing reaction givescompounds of general formula VIII. Hydrolysis and decarboxylation ofcompounds of general formula VIII gives compounds of general formula IX.Treatment of compounds of general formula IX with reagents such asphosphoryl chloride or phosphoryl bromide gives compounds of generalformula X. In a substitution reaction of compounds of general formulae Xand XI, compounds of general formula XII are formed. Compounds ofgeneral formula Ia can be prepared from compounds of general formulaeXII and XIII in the presence of a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(PdCl₂(dppf)) and a base such as cesium carbonate or otherSuzuki-Miyaura coupling reaction conditions known to chemists skilled inthe art of organic synthesis.Method 2:

where R₁, R₂, R₃ and R₄ are as described for formula (I), formula Ia isformula (I) with Y1=N−R1, Y2=C and Y3=C, M is a metal, a boronic acidmoiety or a boronic acid ester moiety, and Pg is a protection group suchas para-methoxy benzyl.

Compounds of general formula XV (Scheme 2) can be prepared by treatmentof compounds of general formula X with compounds of general formula XIVin the presence of a base such as but not limited to cesium fluoride orN,N-diisopropylethylamine. Compounds of general formula XVI can beprepared from compounds of general formulae XV and XIII in the presenceof a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula XVII can be prepared by thedeprotection of compounds of general formula XVI. If the protectiongroup is para-methoxy benzyl, the deprotection can be performed bytreatment with an acid such as trifluoroacetic acid. Compounds ofgeneral formula Ia can be prepared by reductive amination of compoundsof general formula XVII with the appropriate aldehyde such as compoundsof general formula XVIII.

Method 3:

where R₁, R₂, R₃ and R₄ are as described for formula (I); formula Ib isformula (I) with Y1=C−R1, Y2=N and Y3=C; R is an alkyl group such asmethyl or ethyl, M is a metal, a boronic acid moiety or a boronic acidester moiety, and X is a halogen such as chlorine or bromine.

Compounds of general formula XX can be prepared by nitration ofcompounds of general formula XIX by using a reagent such as sodiumnitrite. Reduction of compounds of general formula XX using conditionssuch as hydrogen and palladium gives compounds of general formula XXI.Compounds of general formula XXIII can be prepared from compounds ofgeneral formulae XXI and XXII in the presence of a base such astriethylamine. N-amination of compounds of general formula XXIII using abase such as LiHMDS (lithium bis(trimethylsilyl)amide) and an aminationreagent such as (aminooxy)diphenylphosphine oxide gives compounds ofgeneral formula XXIV. Acylation of compounds of general formula XXIVwith compounds of general formula XXV gives compounds of general formulaXXVI.

Treatment of compounds of general formula XXVI with a base such assodium Cert-butoxide gives compounds of general formula XXVII.Hydrolysis of compounds of general formula XXVII using an aqueous basesuch as sodium hydroxide followed by decarboxylation gives compounds ofgeneral formula XXVIII. Treatment of compounds of general formula XXVIIIwith reagents such as phosphoryl chloride or phosphoryl bromide givescompounds of general formula XXIX. In a substitution reaction ofcompounds of general formulae XXIX and XI, compounds of general formulaXXX are formed. Compounds of general formula Ib can be prepared fromcompounds of general formulae XXX and XIII in the presence of apalladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(PdCl₂(dppf)) and a base such as cesium carbonate or otherSuzuki-Miyaura coupling reaction conditions known to chemists skilled inthe art of organic synthesis.

Method 4:

where R₁, R₂, R₃ and R₄ are as described for formula (I), formula Ib isformula (I) with Y1=C−R1, Y2=N and Y3=C, M is a metal, a boronic acidmoiety or a boronic acid ester moiety, Pg is a protection group such aspara-methoxy benzyl, and X is a halogen such as chlorine or bromine.

Compounds of general formula XXXI (Scheme 4) can be prepared bytreatment of compounds of general formula XXIX with compounds of generalformula XIV in the presence of a base such as but not limited to cesiumfluoride or N,N-diisopropylethylamine.

Compounds of general formula XXXII can be prepared from compounds ofgeneral formulae XXXI and XIII in the presence of a palladium catalystsuch as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichlorideand a base such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula XXXIII can be prepared by thedeprotection of compounds of general formula XXXII. If the protectiongroup is para-methoxy benzyl, the deprotection can be performed bytreatment with an acid such as trifluoroacetic acid. Compounds ofgeneral formula Ib can be prepared by reductive amination of compoundsof general formula XXXIII with the appropriate aldehyde such ascompounds of general formula XVIII.

Method 5:

where Y₁, Y₂, Y₃, R₁, R₂, R₃ and R₄ are as described for formula (I). Pgis a protecting group such as p-methoxybenzyl and Lg is a leaving groupsuch as chlorine, bromine, iodine, 4-methylbenzenesulfonate ormethanesulfonate.

Compounds of general formula XXXV (Scheme 5) can be prepared bydeprotonation of compounds of general formula XVI or XXXXII with a basesuch as sodium hydride followed by alkylation with compounds of generalformula XXXIV. Compounds of general formula I can be prepared by removalof the protecting group (Pg) using reaction conditions known to chemistsskilled in the art of organic synthesis, e.g. by treatment withtrifluoroacetic acid when Pg is p-methoxybenzyl.

LC-MS Methods

Method A:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method B:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=95:5 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method C:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method D:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=85:15 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method E:

An Agilent 1200 LCMS system with ELS detector was used. WatersXbridge-C18, 50×2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.96:0.04) andB=acetonitrile/trifluoroacetic acid (99.98:0.02); Method: Lineargradient elution with A:B=90:10 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method F:

An Agilent 1200 LCMS system with ELS detector was used. WatersXbridge-C18, 50×2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.96:0.04) andB=acetonitrile/trifluoroacetic acid (99.98:0.02); Method: Lineargradient elution with A:B=99:1 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Preparation of Intermediates

Intermediate: ethyl 2-cyano-3-methoxy-4-methylpent-2-enoate

Ethyl 2-cyanoacetate (12.8 g, 113 mmol, 12.1 mL),1,1,1-trimethoxy-2-methyl-propane (25.2 g, 170 mmol) and acetic acid(0.5 mL) were stirred at 120° C. for 4 days under a nitrogenatomosphere. The mixture was concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethyl acetate=20:1to give ethyl 2-cyano-3-methoxy-4-methylpent-2-enoate (17.7 g).

Intermediate: ethyl5-amino-3-isopropyl-1-methyl-1H-pyrazole-4-carboxylate

Methyl hydrazine (20.5 g, 178 mmol, 40 w %) was added dropwise to asolution of ethyl 2-cyano-3-methoxy-4-methyl-pent-2-enoate (12.2 g, 62mmol) in ethanol (130 mL) at 0° C. The reaction was stirred for 90minutes at 0° C., warmed to 70° C. over 60 minutes and agitated at 70°C. for 12 hours. The mixture was concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethyl acetate=2:1to give ethyl 5-amino-3-isopropyl-1-methyl-pyrazole-4-carboxylate (8.5g).

Intermediate: ethyl4,6-dihydroxy-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine-5-carboxylate

Under a nitrogen atmosphere, diethyl propanedioate (5.3 g, 33 mmol) wasadded to a solution of sodium ethoxide, freshly prepared from sodium(827 mg, 36 mmol) in ethanol (8 mL) at room temperature, and the mixturewas stirred at room temperature for 0.5 hour. Ethyl5-amino-3-isopropyl-1-methyl-pyrazole-4-carboxylate (2 g, 9 mmol) wasadded and the mixture was stirred at 100° C. for 12 hours. The mixturewas concentrated and the residue was diluted with water (80 mL) andextracted with dichloromethane (30 mL×2). The aqueous layer was adjustedto pH=5 with aqueous 2N HCl. The resulting mixture was filtered and thefilter cake was washed with water (15 mL×2), and dried to give ethyl4,6-dihydroxy-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine-5-carboxylate(2.2 g).

Intermediate: 3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-4,6-diol

A mixture of ethyl4,6-dihydroxy-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine-5-carboxylate(1.7 g, 6.1 mmol) in aqueous 4N NaOH (17 mL) was stirred at 110° C. for6 hours. The reaction mixture was cooled to 0° C. and aqueous saturatedKHSO₄ was added to adjust the pH=1. The resulting mixture was filteredand the residue was washed with water (20 mL×2), The residue was driedunder vacuum to give3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine-4,6-diol (1.3 g).

¹H NMR (d₆-DMSO 400 MHz): δ 11.10 (brs, 2H), 5.43 (s, 1H), 3.71 (s, 3H),3.25-3.18 (m, 1H), 1.24 (d, J=6.8 Hz, 6H).

Intermediate:4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine

A mixture of 3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-4,6-diol(200 mg, 1 mmol) in POCl₃ (2 mL) was stirred at 80° C. for 18 hours. Themixture was concentrated and then water (10 mL) was added slowly,followed by addition of aqueous saturated NaHCO₃ to adjust pH=7. Theaqueous layer was extracted with dichloromethane (50 mL×3), the combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith petroleum ether:ethyl acetate=30:1 to give4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine (150 mg).

Intermediate:6-chloro-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

To a solution of4,6-dichloro-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine (300 mg, 1mmol) in NMP (1 mL) was added CsF (373 mg, 2 mmol) and(4-methoxyphenyl)methanamine (202 mg, 1 mmol). The mixture was stirredat 100° C. for 18 hours. The reaction mixture was filtered and theresidue was washed with ethyl acetate (15 mL×2), the combined filtrateswere concentrated. The crude mixture of6-chloro-3-isopropyl-N-[(4-methoxyphenyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine(424 mg) was used into the next step without further purification.

Intermediate:6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of6-chloro-3-isopropyl-N-[(4-methoxyphenyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine(424 mg, 1 mmol), (2-ethoxy-3-pyridyl)boronic acid (410 mg, 2 mmol),Pd(dppf)Cl₂ (225 mg, 0.3 mmol), Cs₂CO₃ (1 g, 3 mmol) in dioxane (3 mL)and water (1 mL) was degassed and purged with nitrogen 3 times, and thenthe mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Water (50 mL) was added and the mixture was extracted withethyl acetate (60 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethyl acetate=3:1to 2:1 to give6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxyphenyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine(500 mg).

Intermediate:6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxyphenyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine(500 mg, 1 mmol) in trifluoroacetic acid (5 mL) was stirred at 60° C.for 18 hours The mixture was concentrated and the residue was dissolvedin ethyl acetate (200 mL). The resulting mixture was washed with aqueoussaturated NaHCO₃ (70 mL), brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith petroleum ether:ethyl acetate=3:1 to 2:1 to give6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amine(360 mg).

Intermediate: ethyl acetimidate hydrochloride

To a cooled (0° C.) solution of acetonitrile (10 g, 244 mmol) in drymethanol (15 mL) was added acetyl chloride (23.0 g, 292 mmol) dropwise.The mixture was stirred at 0° C. for 3 hours. The mixture wasconcentrated and methyl Cert-butyl ether (50 mL) was added. The mixturewas stirred at room temperature for 30 minutes. The mixture was filteredand the filter cake was washed with methyl Cert-butyl ether (50 mL) anddried under vacuum to give ethyl acetimidate hydrochloride (13 g).

Intermediate: ethyl 4-methyl-2-nitro-3-oxopentanoate

To a solution of ethyl 4-methyl-3-oxopentanoate (20 g, 126.4 mmol) inacetic acid (30 mL) was dropwise added a solution of NaNO₂ (12.2 g, 177mmol) in water (30 mL). Then water (70 mL) was added. The mixture wasstirred at room temperature for 16 hours. Ethyl acetate (300 mL) wasadded and the organic layer was washed with aqueous saturated NaHCO₃(500 mL), water (200 mL), brine (200 mL) and dried over Na₂SO₄, filteredand concentrated to give ethyl 4-methyl-2-nitro-3-oxopentanoat (22.9 g).

¹H NMR (CDCl₃ 400 MHz): δ 4.41-4.35 (m, 3H), 3.45-3.36 (m, 1H),1.37-1.34 (m, 3H), 1.16-1.14 (m, 6H).

Intermediate: ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride

To a cooled (0° C.) solution of ethyl 4-methyl-2-nitro-3-oxopentanoate(22.9 g, 113 mmol) in dry methanol (150 mL) was added acetyl chloride(17.7 g, 226 mmol) dropwise. The mixture was stirred at 0° C. for 1hour. Then Pd/C (4 g, 5.9 mmol) (10% Pd with 50% of water) was addedunder nitrogen. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (50 psi) at roomtemperature for 16 hours. The mixture was filtered through celite andthe filtrate was concentrated to give ethyl2-amino-4-methyl-3-oxopentanoate hydrochloride (20 g).

¹H NMR (d₆-DMSO 400 MHz): δ 8.93 (brs, 3H), 5.46 (s, 1H), 4.30-4.24 (m,2H), 3.17-3.10 (m, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H),1.03 (d, J=6.4 Hz, 3H).

Intermediate: ethyl 4-isopropyl-2-methyl-1H-imidazole-5-carboxylate

To a cooled (0° C.) solution of ethyl acetimidate hydrochloride (11.29g, 103.0 mmol) in ethanol (50 mL) was dropwise added triethylamine(13.03 g, 128.8 mmol). Then a solution of ethyl2-amino-4-methyl-3-oxopentanoate hydrochloride (5.40 g, 25.8 mmol) inethanol (50 mL) was added at 0° C. and the mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated. The residue wasdissolved in ethyl acetate (20 mL) and washed with water (20 mL×2),brine (20 mL), dried over Na₂SO₄, filtered and concentrated to giveethyl 4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.30 g).

¹H NMR (CDCl₃ 400 MHz): δ 4.33 (q, J=6.8 Hz, 2H), 3.63 (brs, 1H), 2.42(s, 3H), 1.37 (t, J=7.2 Hz, 3H), 1.27 (d, J=7.2 Hz, 6H).

Intermediate: ethyl1-amino-4-isopropyl-2-methyl-1H-imidazole-5-carboxylate

To a cooled (−10° C.) solution of ethyl4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.72 g, 19.0 mmol) inDMF (30 mL) was added a solution of LiHMDS (lithiumhexamethyldisilazide) (1 M in THF, 20.86 mL). The mixture was stirred at−10° C. for 30 minutes. Then a solution of (aminooxy)diphenylphosphineoxide (5.31 g, 22.8 mmol) in DMF (20 mL) was added dropwise. The mixturewas stirred at −10° C. for 1 hour. Water (50 mL) was added and themixture was extracted with ethyl acetate (50 mL×2). The organic layerwas washed with water (50 mL×3), brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give ethyl1-amino-4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.07 g).

Intermediate: ethyl4-isopropyl-1-(3-methoxy-3-oxopropanamido)-2-methyl-1H-imidazole-5-carboxylate

To a cooled (0° C.) solution of ethyl1-amino-4-isopropyl-2-methyl-1H-imidazole-5-carboxylate (3.07 g, 14.5mmol) in dichloromethane (30 mL) was added methyl3-chloro-3-oxopropanoate (2.18 g, 16.0 mmol) dropwise. The mixture wasstirred at 0° C. for 0.5 hour. Water (5 mL) was added. The mixture wasconcentrated. The residue was purified by flash chromatography on silicagel (10% to100% ethyl acetate in petroleum ether) to give ethyl4-isopropyl-1-(3-methoxy-3-oxopropanamido)-2-methyl-1H-imidazole-5-carboxylate(3.6 g).

¹H NMR (CDCl₃ 400 MHz): δ 11.95 (brs, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.79(s, 3H), 3.76-3.70 (m, 3H), 2.70 (s, 3H), 1.42-1.36 (m, 9H).

Intermediate: ethyl2,4-dihydroxy-5-isopropyl-7-methylimidazo[1,5-b]pyridazine-3-carboxylate

To a solution of ethyl4-isopropyl-1-(3-methoxy-3-oxopropanamido)-2-methyl-1H-imidazole-5-carboxylate(2.91 g, 9.35 mmol) in THF (10 mL) was added t-BuOK (3.15 g, 28.0 mmol).The mixture was stirred at room temperature for 1 hour. Water (20 mL)was added and the mixture was acidified to pH=2 by aqueous 1N HCl. Themixture was extracted with ethyl acetate (50 mL×2). The combined organiclayers were washed with water (50 mL), brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give ethyl2,4-dihydroxy-5-isopropyl-7-methylimidazo[1,5-b]pyridazine-3-carboxylate(2.40 g)

Intermediate: 5-isopropyl-7-methylimidazo[1,5-b]pyridazine-2,4-diol

A solution of ethyl2,4-dihydroxy-5-isopropyl-7-methylimidazo[1,5-b]pyridazine-3-carboxylate(1.90 g, 7.16 mmol) in aqueous NaOH (4N, 20 mL) was heated at 100° C.for 3 hours. The mixture was cooled to room temperature and acidified topH=3 with a aqueous saturated KHSO₄ solution. The mixture was filteredand the filter cake was washed with water (100 mL) and dried undervacuum to give 5-isopropyl-7-methylimidazo[1,5-b]pyridazine-2,4-diol(800 mg).

¹H NMR (d₆-DMSO 400 MHz): δ 5.52 (s, 1H), 3.60-3.50 (m, 1H), 2.48 (s,3H), 1.23 (d, J=7.2 Hz, 6H).

Intermediate: 2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine

To a solution of 5-isopropyl-7-methylimidazo[1,5-b]pyridazine-2,4-diol(500 mg, 2.41 mmol) in dry toluene (5 mL) was addeddiisopropylethylamine (623 mg, 4.82 mmol) and POCl₃ (1.48 g, 9.64 mmol).The mixture was heated at 120° C. in a sealed tube for 16 hours. Themixture was cooled to room temperature and water (5 mL) was added. Themixture was adjusted to pH=7 by addition of aqueous saturated NaHCO₃solution and extracted with ethyl acetate (20 mL). The organic layer waswashed with water (20 mL), brine (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography onsilica gel (10% to 20% ethyl acetate in petroleum ether) to give2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine (400 mg).

Intermediate: 2,4-dibromo-5-isopropyl-7-methylimidazo[1,5-b]pyridazine

2,4-Dibromo-5-isopropyl-7-methylimidazo[1,5-b]pyridazine was prepared ina similar way from 5-isopropyl-7-methylimidazo[1,5-b]pyridazine-2,4-dioland POBr₃.

Intermediate:2-chloro-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine

To a solution of2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine (250 mg, 1.02mmol) in NMP (5 mL) was added p-methoxybenzylamine (168 mg, 1.22 mmol)and CsF (310 mg, 2.04 mmol). The mixture was heated at 100° C. for 16hours. The mixture was cooled to room temperature and water (5 mL) wasadded. The mixture was extracted with ethyl acetate (20 mL×2). Theorganic layer was washed with water (20 mL×3), brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel (10% to 50% ethyl acetate in petroleumether) to give2-chloro-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(250 mg).

¹H NMR (CDCl₃ 400 MHz): δ 7.28 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz,2H), 5.23 (s, 1H), 5.30-5.28 (m, 1H), 4.40 (d, J=4.2 Hz, 2H), 3.84 (s,3H), 3.13-3.06 (m, 1H), 2.63 (s, 3H), 1.37 (d, J=6.8 Hz, 6H).

Intermediate:2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine

To a solution of2-chloro-5-isopropyl-N-[(4-methoxyphenyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine(250 mg, 0.72 mmol) in dioxane (4 mL) and water (2 mL) was added(2-ethoxypyridin-3-yl)boronic acid (182 mg, 1.09 mmol), Cs₂CO₃ (472 mg,1.45 mmol) and Pd(dppf)Cl₂ (53 mg, 0.07 mmol). The mixture was degassedwith nitrogen and heated under microwave irradiation at 100° C. for 1hour. The mixture was cooled to room temperature and extracted withethyl acetate (20 mL×2). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The residue was purified byflash chromatography on silica gel (10% to 50% ethyl acetate inpetroleum ether) to give2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(290 mg).

Intermediate: benzyl (cyanomethyl)carbamate

To a solution of NaOH (11 g, 0.26 mol) in water (170 mL) was added2-aminoacetonitrile hydrochloride (24 g, 0.26 mol) in portions over 30min. The mixture was stirred for 30 minutes at which time dioxane (20mL) was added and the mixture cooled to 0° C. Benzyl carbonochloridate(23 g, 132 mmol) was added dropwise via an additional funnel over 1hour. The cooling bath was removed and the mixture stirred for 12 hoursat room temperature. To the mixture was added aqueous HCl (6N) untilpH=3, the aqueous layer extracted with dichloromethane (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (ethyl acetate/petroleum ether) toafford (19 g).

Intermediate: benzyl ((2H-tetrazol-5-yl)methyl)carbamate

A mixture of benzyl (cyanomethyl)carbamate (5.0 g, 26 mmol), NaN₃ (3.4g, 53 mmol), ZnBr₂ (3.3 g, 15 mmol) and isopropyl alcohol (30 mL) inwater (60 mL) was stirred at 100° C. for 12 hours. The mixture waspoured into water (250 mL), and aqueous KHSO₄ was added until pH=2. Theaqueous phase was extracted with ethyl acetate (100 mL×3). The combinedorganic phase were washed with brine (80 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford benzyl((2H-tetrazol-5-yl)methyl)carbamate (6.0 g).

Intermediate: benzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate

To a mixture of benzyl ((2H-tetrazol-5-yl)methyl)carbamate (2.0 g, 8.6mmol) and K₂CO₃ (2.4 g, 17 mmol) in DMF (20 mL) was added methyl iodide(1.8 g, 13 mmol) at 0° C., and it was stirred at 30° C. for 12 hours.The mixture was filtered and the filtrate was concentrated under vacuum.The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=10/1 to 1/1) to afford benzyl((2-methyl-2H-tetrazol-5-yl)methyl)carbamate (560 mg).

Intermediate: (2-methyl-2H-tetrazol-5-yl)methanamine

To a solution of benzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate(560 mg, 2.3 mmol) in methanol (10 mL) was added Pd/C (wet, 5 mg, 10%Pd/C) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (15 psi) at roomtemperature for 12 hours. The mixture was filtered and the filtrate wasconcentrated under vacuum to afford(2-methyl-2H-tetrazol-5-yl)methanamine (200 mg). Intermediate:(2-methyl-2H-1,2,3-triazol-4-yl)methanol.

A solution of methyl 2-methyl-2H-1,2,3-triazole-4-carboxylate (400 mg,2.83 mmol) in THF (4 mL) was added to a mixture of LiAlH₄ (323 mg, 8.50mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred at 0° C.for 2 hours. The solution was quenched with NaOH (aq. 1N, 3 mL) at 0° C.The mixture was filtered and concentrated under vacuum to afford(2-methyl-2H-1,2,3-triazol-4-yl)methanol.

Intermediate: 4-(bromomethyl)-2-methyl-2H-1,2,3-triazole

To a solution of (2-methyl-2H-1,2,3-triazol-4-yl)methanol (280 mg, 2.48mmol) in dichloromethane (30 mL) was added PBr₃ (1.3 g, 4.95 mmol) at 0°C. The resulting mixture was stirred at 30° C. for 12 hours. Thesolution was poured into ice-water (10 mL), the aqueous phase wasextracted with ethyl acetate (10 mL×3). The combined organic phases werewashed with brine (10 mL×1), dried with anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0, 2/1) to afford4-(bromomethyl)-2-methyl-2H-1,2,3-triazole.

Intermediate: 4-(chloromethyl)-1-methyl-1H-1,2,3-triazole

A solution of (1-methyl-1H-1,2,3-triazol-4-yl)methanol (0.1 g, 0.88mmol) in SOCl₂ (10 mL) was stirred at 80° C. for 1 hour. The solutionwas concentrated under vacuum. The residue was diluted withdichloromethane (10 mL) and washed with NaHCO₃ (aq.) until pH=7. Theorganic phase was washed with brine (5 mL×1), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford4-(chloromethyl)-1-methyl-1H-1,2,3-triazole.

Intermediate: tert-butyl((3-methyl-1,2,4-oxadiazol-5-yl)methyl)carbamate

Molecular sieve 4 Å (500 mg) was added to a solution ofN-hydroxyacetamidine (1.09 g, 14.76 mmol) in THF (20 mL). The mixturewas stirred at 20° C. for 30 minutes. Then NaH (590 mg, 14.8 mmol, 60%in mineral oil) was added and the mixture was heated at 50° C. for 30minutes. Then the mixture was cooled to 20° C. and ethyl2-((tert-butoxycarbonyl)amino)acetate (1 g, 4.92 mmol) was added. Themixture was heated at 80° C. for 2 hours. Water (5 mL) was added. Themixture was extracted with ethyl acetate (20 mL×2). The combined organicphases were washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on silica gel (0%˜50% ethyl acetate in petroleum ether)to give tert-butyl ((3-methyl-1,2,4-oxadiazol-5-yl)methyl)carbamate.

Intermediate: (3-methyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride

To a solution of tert-butyl((3-methyl-1,2,4-oxadiazol-5-yl)methyl)carbamate (400 mg, 1.88 mmol) indichloromethane (4 mL) was added HCl/dioxane (4 M, 4 mL). The mixturewas stirred at 20° C. for 1 h. The mixture was concentrated to give(3-methyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride.

Intermediate: 1-methyl-1H-1,2,4-triazole-3-carbaldehyde

To a mixture of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (400 mg, 3.54mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane(10 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56mg, 354 μmol. The mixture was stirred at 15-20° C. for 2h. The mixturewas concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:2) to give1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

Intermediate:2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 3-bromo-2-propoxy-pyridine (200 mg, 0.093 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(282 mg, 1.11 mmol), KOAc (182 mg, 1.85 mmol), Pd(dppf)Cl₂ (135 mg, 0.18mmol) in dioxane (3 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 80° C. for 2 hours under a N₂atmosphere. The mixture was filtered and the residue was washed withdioxane (5 mL×2), the combined filtrates were concentrated. The crudeproduct2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasused into the next step without further purification.

Intermediate: 4-(chloromethyl)-2-methoxypyridine

To a solution of (2-methoxypyridin-4-yl)methanol (200 mg, 1.44 mmol) indichloromethane (5 mL) was added SOCl₂ (513 mg, 4.31 mmol) at 0° C. Themixture was stirred at 20° C. for 2 hours. The mixture was concentrated.The residue was dissolved in ethyl acetate (20 mL) and H₂O (20 mL). Theorganic layer was washed with sat. aq. NaHCO₃ (20 mL), H₂O (20 mL),brine (20 mL), dried over Na₂SO₄, filtered and concentrated to give4-(chloromethyl)-2-methoxypyridine.

Intermediate: diethyl 2-((tert-butoxycarbonyl)amino)malonate

To a solution of diethyl 2-aminomalonate hydrochloride (50 g, 236 mmol)in H₂O (300 mL) and dioxane (440 mL) was slowly added NaHCO₃ (21 g, 248mmol) at 20° C. When the solution became clear, DMAP (289 mg, 2 mmol)was added followed by dropwise addition of a solution of Boc₂O (54 g,248 mmol) in dioxane (160 mL). The mixture was stirred at 20° C. for 12hours. The mixture were concentrated. The residue was dissolved in ethylacetate. The organic phase was washed with solution of 5% KHSO₄ (aq.),sat. aq. NaHCO₃, water, and brine, and dried over anhydrous Na₂SO₄, thenfiltered and concentrated to give diethyl2-((tert-butoxycarbonyl)amino)malonate.

Intermediate: 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropanoicacid

To a solution of diethyl 2-((tert-butoxycarbonyl)amino)malonate (30 g,109 mmol) in EtOH/H₂O (675 mL/75 mL), a solution of KOH (7 g, 120 mmol)in H₂O (45 mL) was added dropwise while stirring at 20° C. The reactionmixture was stirred at 20° C. for 12 hours. The ethanol was removed invacuo and the residue was acidified to pH=2 by 2N HCl (aq.) and washedwith dichloromethane. The organic layer was washed with brine and driedover Na₂SO₄, filtered and concentrated to give2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropanoic acid.

Intermediate: ethyl2-((tert-butoxycarbonyl)amino)-4-methyl-3-oxohexanoate

A mixture of 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropanoic acid(41 g, 166 mmol), triethylamine (34 g, 340 mmol) and MgCl₂ (17 g, 174mmol) in MeCN (320 mL) was stirred at 0° C. for 2.5 hours. Then asolution of (±)-2-methylbutanoyl chloride (10 g, 83 mmol) in MeCN (80mL) was added to the resulting mixture at 0° C. The mixture was stirredat 20° C. for 12 hours. The reaction mixture was quenched by additioncitric acid (sat. aq.) (50 mL) at 0° C., and extracted with ethylacetate (10 mL×3). The combined organic layers were washed with citricacid (sat. aq. 50 mL), NaHCO₃ (sat. aq. 50 mL×2), and brine (100 mL),dried over Na₂SO₄ filtered and concentrated under reduced pressure. Theresidue was purified by flash silica gel chromatography (0%˜10% ethylacetate in petroleum ether) to give ethyl2-((tert-butoxycarbonyl)amino)-4-methyl-3-oxohexanoate.

Intermediate: ethyl 2-amino-4-methyl-3-oxohexanoate hydrochloride

A solution of ethyl2-((tert-butoxycarbonyl)amino)-4-methyl-3-oxohexanoate (16 g, 56 mmol)in HCl/ethyl acetate (4 M, 160 mL) was stirred at 20° C. for 12 hours.The solution was concentrated to give ethyl2-amino-4-methyl-3-oxohexanoate hydrochloride.

Intermediates:(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine

(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-aminewas prepared in a similar way as2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-aminefrom (±)-ethyl 2-amino-4-methyl-3-oxohexanoate hydrochloride.(+)-5-(sec-Butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(SFC: t_(R)=3.850 minutes, ee %=99.2%; [α]_(D) ²⁰+2.67 (c=0.2, MeOH))and(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(SFC: t_(R)=4.177 minutes, ee %=98.3%; [α]_(D) ²⁰ −11.0 (c=0.2, MeOH))were obtained after chiral SFC separation (SFC conditions:Insturment:Waters wpc2; Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um;Mobile phase: A: CO₂ B:iso-propanol (0.05% DEA); Gradient: from 5% to40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min;Flow rate: 2.5 mL/min; Column temp.: 35° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm).

Intermediate:3-isopropyl-N-(4-methoxybenzyl)-1-methyl-6-(2-propoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

3-isopropyl-N-(4-methoxybenzyl)-1-methyl-6-(2-propoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-aminewasprepared in a similar way as2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-aminefrom 4,6-dichloro-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridine and2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

Intermediate: 5-iodoimidazo[1,5-a]pyridine

A mixture of imidazo[1,5-a]pyridine (2 g, 17 mmol) in THF (150 mL) wascooled to −78° C. and n-butyllithium (2.5 M, 14 mL) was added dropwise.The reaction mixture was stirred for 30 minutes at −78° C., then thesolution was warmed to 20° C. and stirred for 30 minutes. The solutionwas cooled to 0° C., quenched with 1₂ (4.5 g, 18 mmol) in THF (5 mL) andstirred for 2 hours. The resulting mixture was diltuted with water andextracted with dichloromethane (3×50 mL). The organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash silica gel chromatography (0%˜100% ethyl acetate in petroleumether) to give 5-iodoimidazo[1,5-a]pyridine.

Intermediate: imidazo[1,5-a]pyridine-5-carbonitrile

To a stirred solution of 5-iodoimidazo[1,5-a]pyridine (750 mg, 3.1 mmol)in dimethylacetamide (15 mL) under an argon atmosphere were addedZn(CN)₂ (235 mg, 2.0 mmol), Pd(dba)₂ (71 mg, 0.12 mmol), DPPF (136 mg,0.25 mmol) at 25° C. The reaction mixture was stirred for 30 minutes at100° C. (heating by microwaves). The reaction mixture was diluted withwater (30 mL) and extracted with ethyl acetate (2×45 mL). The combinedorganic extracts were washed with water (40 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography (0%˜50% ethyl acetate in petroleum ether) to giveimidazo[1,5-a]pyridine-5-carbonitrile.

Intermediate: tert-butyl (imidazo[1,5-a]pyridin-5-ylmethyl)carbamate

To a solution of Raney-Ni (1.5 g, 17 mmol) in EtOH (10 mL) was addedimidazo[1,5-a]pyridine-5-carbonitrile (0.5 g, 3.5 mmol) and Boc₂O (839mg, 3.8 mmol), then the mixture was stirred at 25° C. under H₂ (45 Psi)for 4 hours. The mixture was filtered and concentrated. The residue waspurified by flash silica gel chromatography (0%˜100% ethyl acetate inpetroleum ether) to give tert-butyl(imidazo[1,5-a]pyridin-5-ylmethyl)carbamate.

Intermediate: imidazo[1,5-a]pyridin-5-ylmethanamine

A mixture of tert-butyl (imidazo[1,5-a]pyridin-5-ylmethyl)carbamate (94mg, 0.38 mmol) in HCl/ethyl acetate (2 mL) was stirred at 20° C. for 0.5hour. The reaction mixture was concentrated to giveimidazo[1,5-a]pyridin-5-ylmethanamine.

Intermediate: imidazo[1,2-a]pyridine-5-carbonitrile

A mixture of 5-bromoimidazo[1,2-a]pyridine (500 mg, 2.54 mmol), Zn(CN)₂(328 mg, 2.79 mmol), and Pd(dppf)Cl₂ (186 mg, 0.254 mmol) in NMP (30 mL)was stirred at 140° C. for 2 hour under N₂. The mixture was poured intoNaHCO₃ (aq. 100 mL) extracted with ethyl acetate (30 mL×3). The combinedorganic phases were washed with brine (50 mL×3), dried with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 1:1) toafford imidazo[1,2-a]pyridine-5-carbonitrile

Intermediate: tert-butyl (imidazo[1,2-a]pyridin-5-ylmethyl)carbamate

To a solution of imidazo[1,2-a]pyridine-5-carbonitrile (200 mg, 1.40mmol) and Boc₂O (366 mg, 1.68 mmol,) in MeOH (30 mL) was added Raney-Ni(22 mg) at 30° C. The mixture was stirred at 30° C. for 12 hours underH₂ (45 Psi). The mixture was filtered and the filtrate was concentratedto afford tert-butyl (imidazo[1,2-a]pyridin-5-ylmethyl)carbamate.

Intermediate: imidazo[1,2-a]pyridin-5-ylmethanamine hydrochloride

A mixture of tert-butyl (imidazo[1,2-a]pyridin-5-ylmethyl)carbamate (350mg) in HCl/ethyl acetate (4M, 20 mL) was stirred at 10° C. for 1 hour.The mixture was concentrated to affordimidazo[1,2-a]pyridin-5-ylmethanamine hydrochloride, which was used intothe next step without further purification.

Preparation of Compounds of the Invention

Example 1:2-(2-ethoxypyridin-3-yl)-S-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methyl)imidazo[1,5-b]pyridazin-4-amine

Preparation of2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amine

A solution of2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(290 mg, 0.67 mmol) in trifluoroacetic acid (5 mL) was heated at 60° C.for 16 hours. The mixture was concentrated. Water (10 mL) was added tothe residue. The pH of the mixture was adjusted to pH=7 by addition ofaqueous saturated NaHCO₃ solution. The mixture was extracted with ethylacetate (20 mL×2). The combined organic layers were washed with water(20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash chromatography on silica gel (10% to50% ethyl acetate in petroleum ether) to give2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amine(150 mg).

Preparation of2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methylene)imidazo[1,5-b]pyridazin-4-amine

To a solution of2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amine(50 mg, 0.16 mmol) in dry THF (2 mL) was added1-methyl-1H-imidazole-4-carbaldehyde (35 mg, 0.32 mmol) and Ti(i-PrO)₄(91 mg, 0.32 mmol). The mixture was heated at 80° C. for 32 hours. Thesolution of2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methylene)imidazo[1,5-b]pyridazin-4-amine(65 mg) in THF (2 mL) was directly used for the next step.

Preparation of2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methypimidazo[1,5-b]pyridazin-4-amine

A reaction mixture from the previous step containing2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methylene)imidazo[1,5-b]pyridazin-4-amine(65 mg, 0.16 mmol) in ethanol (2 mL) and THF (5 mL) was cooled to 0° C.and then NaBH₄ (30 mg, 0.80 mmol) was added in portions. The mixture wasstirred at 0° C. for 1 hour. Water (5 mL) was added the mixture wasfiltered through celite, the filtrate was concentrated. The residue waspurified by preparative HPLC to give2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((1-methyl-1H-imidazol-4-yl)methypimidazo[1,5-b]pyridazin-4-amine(15 mg).

¹H NMR (CDCl₃ 400 MHz): δ 8.20 (dd, J=2.0, 4.8 Hz, 1H), 8.03 (dd, J=2.0,7.6 Hz, 1H), 7.43 (s, 1H), 6.99 (dd, J=4.8, 7.2 Hz, 1H), 6.86 (s, 1H),6.09 (s, 1H), 5.59 (brs, 1H), 4.48-4.41 (m, 4H), 3.68 (s, 3H), 3.33-3.26(m, 1H), 2.68 (s, 3H), 1.42 (d, J=7.2 Hz, 6H), 1.38 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=2.202 minutes (Method B), m/z=406.1 [M+H]⁺.

Example 2:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 2-methyloxazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.29 (d, J=6.8 Hz, 1H), 8.19 (d, J=7.2 Hz,1H), 7.51 (s, 1H), 7.04-7.01 (m, 1H), 6.95 (s, 1H), 5.34 (brs, 1H),4.49-4.44 (m, 4H), 4.04 (s, 3H), 3.34-3.31 (m, 1H), 2.48 (s, 3H)1.48-1.36 (m, 9H). LC-MS: t_(R)=2.114 minutes (Method C), m/z=407.0[M+H]⁺.

Example 3:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=1.6, 7.2 Hz, 1H), 8.20 (dd, J=2.0,4.8 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.05-7.01 (m, 2H), 6.36 (d, J=2.0Hz, 1H), 5.58-5.57 (m, 1H), 4.62 (d, J=4.8 Hz, 2H), 4.49 (q, J=7.2 Hz,2H), 4.05 (s, 3H), 3.37-3.33 (m, 1H), 1.47 (d, J=6.8 Hz, 6H), 1.42 (t,J=6.8 Hz, 3H). LC-MS: t_(R)=2.196 minutes (Method C), m/z=392.1 [M+H]⁺.

Example 4:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 1-methyl-1,2,4-triazole-3-carbaldehyde

¹h NMR (CDCl₃ 400 MHz): δ 8.31 (d, J=7.2 Hz, 1H), 8.20 (d, J=5.2 Hz,1H), 8.05 (s, 1H), 7.04-7.01 (m, 2H), 5.82 (s, 1H), 4.62 (d, J=4.4 Hz,2H), 4.50 (q, J=7.2 Hz, 2H), 4.05 (s, 3H), 3.95 (s, 3H), 3.44-3.41 (m,1H), 1.50 (d, J=6.8 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H) LC-MS: t_(R)=2.115minutes (Method B), m/z=407.1 [M+H]⁺.

Example 5:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 5-methyl-1,2,4-oxadiazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=2.0, 7.2 Hz, 1H), 8.20 (dd, J=2.0,4.8 Hz, 1H), 7.04-7.01 (m, 2H), 5.54 (brs, 1H), 4.66 (d, J=6.4 Hz, 2H),4.50 (q, J=7.2 Hz, 2H), 4.05 (s, 3H), 3.42-3.35 (m, 1H), 2.63 (s, 3H),1.50 (d, J=6.8 Hz, 6H), 1.45 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.113minutes (Method C), m/z=408.0 [M+H]⁺.

Example 6:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 5-methyl-1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz) δ 8.30 (d, J=6.8 Hz, 1H), 8.19 (brs, 1H),7.02-6.99 (m, 2H), 6.07 (s, 1H), 5.53 (brs, 1H), 4.53-4.47 (m, 4H), 4.04(s, 3H), 3.44-3.34 (m, 1H), 2.33 (s, 3H), 1.47 (d, J=6.4 Hz, 6H),1.43-1.40 (m, 3H). LC-MS: t_(R)=2.340 minutes (Method B), m/z=406.1[M+H]⁺.

Example 7:6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 2-methoxypyridine-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.28 (dd, J=2.0, 7.6 Hz, 1H), 8.18-8.14 (m,2H), 7.00 (dd, J=4.8, 7.6 Hz, 1H), 6.90 (d, J=6.0 Hz, 1H), 6.83 (s, 1H),6.76 (s, 1H), 5.31-5.25 (m, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.35 (q, J=7.2Hz, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.37-3.29 (m, 1H), 1.50 (d, J=6.8Hz, 6H), 1.23 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.990 minutes (Method A),m/z=433.0 [M+H]⁺.

Example 8:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylimidazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 1-methylimidazole-4-carbaldehyde

¹h NMR (CDCl₃ 400 MHz): δ 8.20 (dd, J=2.0, 4.8 Hz, 1H), 8.03 (dd, J=2.0,7.6 Hz, 1H), 7.43 (s, 1H), 6.99 (dd, J=4.8, 7.2 Hz, 1H), 6.86 (s, 1H),6.09 (s, 1H), 5.59 (brs, 1H), 4.48-4.41 (m, 4H), 3.68 (s, 3H), 3.33-3.26(m, 1H), 2.68 (s, 3H), 1.42 (d, J=7.2 Hz, 6H), 1.38 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=2.202 minutes (Method B), m/z=406.1 [M+H]⁺.

Example 9:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 2-methyloxazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): 8.22 (dd, J=2.0, 5.2 Hz, 1H), 8.03 (dd, J=2.0,7.2 Hz, 1H), 7.52 (s, 1H), 6.99 (dd, J=5.2, 7.2 Hz, 1H), 6.07 (s, 1H),5.51-5.34 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 4.39 (d, J=5.2 Hz, 2H),3.35-3.13 (m, 1H), 2.69 (s, 3H), 2.48 (s, 3H), 1.44 (d, J=6.8 Hz, 6H),1.36 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.219 minutes (Method C), m/z=407.0[M+H]⁺.

Example 10:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.22 (dd, J=2.0, 4.2 Hz, 1H), 8.04 (dd, J=2.0,7.2 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.00 (dd, J=4.2, 7.6 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 6.13 (s, 1H), 5.72 (brs, 1H), 4.56 (d, J=4.8 Hz, 2H),4.47 (q, J=7.2 Hz, 2H), 3.37-3.30 (m, 1H), 2.71 (s, 3H), 1.46 (d, J=6.8Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.016 minutes (Method C),m/z=392.1 [M+H]⁺.

Example 11:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 1-methyl-1,2,4-triazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.24 (br.s, 1H), 8.06 (br.s, 2H), 7.00 (t,J=4.8 Hz, 1H), 6.13 (s, 1H), 5.92 (br.s, 1H), 4.56 (d, J=3.6 Hz, 2H),4.48 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.43-3.39 (m, 1H), 2.70 (s, 3H),1.48 (d, J=6.4 Hz, 6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.951minutes (Method C), m/z=407.1 [M+H]⁺.

Example 12:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 5-methyl-1,2,4-oxadiazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.22 (d, J=3.6 Hz, 1H), 8.04 (d, J=7.6 Hz,1H), 7.00 (t, J=4.2 Hz, 1H), 6.15 (s, 1H), 5.62 (br s, 1H), 4.60 (d,J=5.6 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 3.33-3.31 (m, 1H), 2.70 (s, 3H),2.64 (s, 3H), 1.47 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS:t_(R)=2.016 minutes (Method C), m/z=392.1 [M+H]⁺.

Example 13:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 5-methyl-1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.22 (dd, J=2.0, 4.8, 1H), 8.04 (dd, J=2.0,7.2 Hz, 1H), 7.00 (dd, J=4.2, 7.6 Hz, 1H), 6.12 (s, 1H), 6.07 (s, 1H),5.69 (br.s, 1H), 4.49-4.44 (m, 4H), 3.37-3.30 (m, 1H), 2.71 (s, 3H),2.35 (s, 3H), 1.46 (d, J=6.8 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS:t_(R)=2.078 minutes (Method C), m/z=406.1 [M+H]⁺.

Example 14:2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 5-methoxypyridine-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.30-8.28 (m, 2H), 8.21 (dd, J=1.6, 4.8 Hz,1H), 8.03 (dd, J=2.0, 7.6 Hz, 1H), 7.22 (s, 1H), 6.99 (dd, J=5.0, 7.3Hz, 1H), 6.08 (s, 1H), 5.31-5.25 (m, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.39(q, J=7.2 Hz, 2H), 3.87 (s, 3H), 3.30-3.21 (m, 1H), 2.71 (s, 3H), 1.46(d, J=7.2 Hz, 6H), 1.29-1.26 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.149minutes (Method D), m/z=433.1 [M+H]⁺.

Example 15:2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 2-methoxypyridine-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23-8.13 (m, 2H), 8.01 (d, J=6.8 Hz, 1H),7.03-6.93 (m, 1H), 6.88 (d, J=4.8 Hz, 1H), 6.75 (s, 1H), 5.96 (s, 1H),5.38 (brs, 1H), 4.54 (d, J=5.6 Hz, 2H), 4.33 (q, J=6.8 Hz, 2H), 3.94 (s,3H), 3.31 (d, J=6.4 Hz, 1H), 2.71 (s, 3H), 1.52-1.46 (m, 6H), 1.20 (t,J=6.8 Hz, 3H). LC-MS: t_(R)=2.381 minutes (Method D), m/z=433.1 [M+H]⁺.

Example 16:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 2-methyloxazole-5-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=4.8, 1.6 Hz, 1H), 8.03 (dd, J=7.6,2.0 Hz, 1H), 7.02-6.99 (m, 1H), 6.93 (s, 1H), 6.13 (s, 1H), 5.18 (brs,1H), 4.53-4.45 (m, 4H), 3.26-3.22 (m, 1H), 2.70 (s, 3H), 2.47 (s, 3H),1.45 (d, J=6.8 Hz, 6H), 1.39 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.329minutes (Method B), m/z=407.0 [M+H]⁺.

Example 17:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methylthiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 2-methylthiazole-5-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=5.2, 2.0 Hz, 1H), 8.04 (dd, J=7.6,2.0 Hz, 1H), 7.59 (s, 1H), 7.02-6.99 (m, 1H), 6.15 (s, 1H), 5.21-5.18(m, 1H), 4.67 (d, J=6.8 Hz, 2H), 4.46 (q, J=5.2 Hz, 2H) 3.23-3.19 (m,1H), 2.71 (s, 3H), 2.70 (s, 3H), 1.44 (d, J=6.8 Hz, 6H), 1.39 (t, J=6.8Hz, 3H). LC-MS: t_(R)=1.822 minutes (Method A), m/z=423.0 [M+H]⁺.

Example 18:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-4-ylmethyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 1H-pyrazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.22 (dd, J=2.0, 4.8 Hz, 1H), 8.04 (dd, J=2.0,7.6 Hz, 1H), 7.68 (s, 2H), 7.00 (dd, J=4.2, 7.6 Hz, 1H), 6.14 (s, 1H),5.06 (brs, 1H), 4.49-4.44 (m, 4H), 3.22-3.17 (m, 1H), 2.70 (s, 3H), 1.41(d, J=6.8 Hz, 6H), 1.37 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.951 minutes(Method C), m/z=407.1 [M+H]⁺.

Example 19:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Preparation of6-chloro-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

To a solution of4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine (50 mg, 0.2mmol) in NMP (1 mL) was added CsF (156 mg, 1 mmol) and(1-methylpyrazol-4-yl)methanamine hydrochloride (54 mg, 0.2 mmol). Themixture was stirred at 100° C. for 36 hours. The reaction mixture wasfiltered and the residue was washed with ethyl acetate (5 mL×2). Thecombined filtrates were concentrated. The crude product6-chloro-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(65 mg) was used in the next step without further purification.

Preparation of6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of6-chloro-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(65 mg, 0.20 mmol), (2-ethoxy-3-pyridyl)boronic acid (68 mg, 0.41 mol),Pd(dppf)Cl₂ (38 mg, 0.05 mmol), Cs₂CO₃ (167 mg, 0.5 mmol) in dioxane (3mL) and water (1 mL) was degassed and purged with nitrogen 3 times, andthen the mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Water (30 mL) was added and the mixture was extracted withethyl acetate (45 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by preparative HPLC to give6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(41 mg).

¹H NMR (CDCl₃ 400 MHz): δ 8.32 (dd, J=2.0, 7.6 Hz, 1H), 8.20 (dd, J=2.0,4.8 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.05-7.01 (m, 2H), 4.96 (brs,1H), 4.48 (q, J=7.2 Hz, 2H), 4.43 (d, J=4.8 Hz, 2H), 4.06 (s, 3H), 3.89(s, 3H), 3.26-3.19 (m, 1H), 1.43 (d, J=6.8 Hz 6H), 1.41-1.38 (m, 3H).LC-MS: t_(R)=1.971 minutes (Method C), m/z=406.1 [M+H]⁺.

Example 20:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methyltetrazol-5-yl)methanamine¹H NMR (CDCl₃ 400 MHz): δ 8.31 (dd, J=7.6, 2.0 Hz, 1H), 8.20 (dd, J=4.8,2.0 Hz, 1H), 7.05-7.03 (m, 2H), 5.67-5.64 (m, 1H), 4.83 (d, J=5.2 Hz,2H), 4.50 (q, J=7.2 Hz, 2H), 4.38 (s, 3H), 4.05 (s, 3H), 3.43-3.34 (m,1H), 1.50 (d, J=6.8 Hz, 6H), 1.45 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.081minutes (Method C), m/z=408.0 [M+H]⁺

Example 21:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (1-methylpyrazol-3-yl)methanamine

¹H NMR (CDCl₃ 400 MHz): δ 8.31 (dd, J=2.0, 7.6 Hz, 1H), 8.20 (dd, J=2.0,5.2 Hz, 1H), 7.60 (s, 1H), 7.06-7.01 (m, 2H), 5.12-5.09 (m, 1H), 4.72(d, J=5.2 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 4.05 (s, 3H), 3.29-3.22 (m,1H), 2.70 (s, 3H), 1.46 (d, J=6.8 Hz, 6H), 1.39 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=1.989 minutes (Method A), m/z=423.0 [M+H]⁺.

Example 22:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (1-methylpyrazol-4-yl)methanamine

¹H NMR (CDCl₃ 400 MHz): δ 8.21 (dd, J=1.6, 4.8 Hz, 1H), 8.03 (dd, J=2.0,7.2 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.99 (dd, J=4.8, 7.6 Hz, 1H),6.12 (s, 1H), 5.01 (brs, 1H), 4.45 (q, J=6.8 Hz, 2H), 4.36 (d, J=4.8 Hz,2H), 3.91 (s, 3H), 3.20-3.13 (m, 1H), 2.68 (s, 3H), 1.41-1.35 (m, 9H).LC-MS: t_(R)=2.004 minutes (Method C), m/z=406.1 [M+H]⁺.

Example 23:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltetrazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methyltetrazol-5-yl)methanamine

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=4.8, 2.0 Hz, 1H), 8.04 (dd, J=7.2,2.0 Hz, 1H), 7.02-6.99 (m, 1H), 6.17 (s, 1H), 5.75-5.72 (m, 1H), 4.78(d, J=5.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 4.38 (s, 3H), 3.41-3.31 (m,1H), 2.70 (s, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=2.052 minutes (Method C), m/z=408.1 [M+H]⁺.

Example 24:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (1-methylpyrazol-3-yl)methanamine

¹H NMR (CDCl₃ 400 MHz): δ 8.22 (dd, J=4.8, 2.0 Hz, 1H), 8.04 (dd, J=7.2,2.0 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.00 (dd, J=7.4, 4.8 Hz, 1H), 6.25(d, J=2.4 Hz, 1H), 6.12 (s, 1H), 5.66 (brs, 1H), 4.44-4.51 (m, 4H), 3.92(s, 3H), 3.37-3.30 (m, 1H), 2.71 (s, 3H), 1.46 (d, J=6.8 Hz, 6H), 1.40(t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.069 minutes (Method C), m/z=406.1[M+H]⁺.

Example 25:6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand 5-methoxypyridine-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.31-8.29 (m, 3H), 8.18 (dd, J=2.0, 5.2 Hz,1H), 7.24 (s, 1H), 7.02 (dd, J=4.8, 7.2 Hz, 1H), 6.95 (s, 1H), 5.20-5.17(m, 1H), 4.62 (d, J=7.0 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.06 (s, 3H),3.85 (s, 3H), 3.33-3.26 (m, 1H), 1.47 (d, J=6.8 Hz, 6H), 1.30 (t, J=7.2Hz, 3H) LC-MS: t_(R)=1.6 minutes (Method A), m/z=433.1 [M+H]⁺.

Example 26:6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-aminePreparation of6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

To a solution of6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine(0.1 g, 0.23 mmol) and t-BuOK (52 mg, 0.46 mmol) in DMSO (5 mL) wasadded 4-(bromomethyl)-2-methyl-2H-1,2,3-triazole (61 mg, 0.35 mmol). Thereaction mixture was stirred at 100° C. for 12 hours. The solution waspoured into ice-water (40 mL) and extracted with ethyl acetate (20mL×3). The combined organic phases were washed with brine (20 mL×1),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toafford6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine.

Preparation of6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

A solution of6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(0.14 g, 0.27 mmol) in TFA (5 mL) was stirred at 60° C. for 12 hours.The solution was concentrated under vacuum, the residue was diluted withdichloromethane (20 mL) and washed with NaHCO₃ (aq.) until pH=8. Theorganic phase was washed with brine (8 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypreparative HPLC to afford6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine.¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=7.2, 2.0 Hz, 1H), 8.19 (dd, J=5.2,2.0 Hz, 1H), 7.58 (s, 1H), 7.03 (dd, J=7.6, 4.8 Hz, 1H), 7.00 (s, 1H),5.39-5.36 (m, 1H), 4.63 (d, J=5.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 4.21(s, 3H), 4.05 (s, 3H), 3.37-3.27 (m, 1H), 1.47 (d, J=6.8 Hz, 6H), 1.40(t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.05 minutes (Method C), m/z=407.1[M+H]⁺.

Example 27:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amine,2-methyloxazole-5-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=2.0, 7.6 Hz, 1H), 8.20 (dd, J=2.0,4.8 Hz, 1H), 7.05-7.00 (m, 2H), 6.92 (s, 1H), 5.10 (brs, 1H), 4.58 (d,J=5.6 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 4.05 (s, 3H), 3.32-3.26 (m, 1H),2.46 (s, 3H), 1.47 (d, J=7.2 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H). LC-MS:t_(R)=2.45 minutes (Method B), m/z=407.1 [M+H]⁺.

Example 28:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand 2-methylthiazole-5-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.31 (dd, J=2.0, 7.6 Hz, 1H), 8.20 (dd, J=2.0,5.2 Hz, 1H), 7.60 (s, 1H), 7.06-7.01 (m, 2H), 5.12-5.09 (m, 1H), 4.72(d, J=5.2 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 4.05 (s, 3H), 3.29-3.22 (m,1H), 2.70 (s, 3H), 1.46 (d, J=6.8 Hz, 6H), 1.39 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=1.99 minutes (Method A), m/z=423 [M+H]⁺.

Example 29:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 26 from6-(2-ethoxypyridin-3-yl)-3-isopropyl-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-amineand 4-(chloromethyl)-1-methyl-1H-1,2,3-triazole

¹H NMR (CDCl₃ 400 MHz): δ 8.33 (dd, J=7.6, 2.0 Hz, 1H), 8.20 (dd, J=4.8,2.0 Hz, 1H), 7.52 (s, 1H), 7.05-7.03 (m, 1H), 7.02 (s, 1H), 5.53 (brs,1H), 4.69 (d, J=5.2 Hz, 2H), 4.47 (q, J=7.2 Hz, 2H), 4.10 (s, 3H), 4.05(s, 3H), 3.37-3.30 (m, 1H), 1.46 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz,3H). LC-MS: t_(R)=1.7 minutes (Method C), m/z=407.1 [M+H]⁺.

Example 30:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand 1H-pyrazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.32 (dd, J=2.0, 7.6 Hz, 1H), 8.19 (dd, J=2.0,4.8 Hz, 1H), 7.68 (s, 2H), 7.05-7.01 (m, 2H), 4.98-4.96 (m, 1H),4.51-4.45 (m, 4H), 4.05 (s, 3H), 3.25-3.21 (m, 1H), 1.43 (d, J=6.8 Hz,6H), 1.41-1.40 (m, 3H). LC-MS: t_(R)=2.24 minutes (Method B), m/z=392[M+H]⁺.

Example 31:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(5-methyl-1,3,4-oxadiazol-2-yl)methanamine oxalate and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=7.2, 2.0 Hz, 1H), 8.20 (dd, J=4.8,2.0 Hz, 1H), 7.05-7.02 (m, 2H), 5.54-5.51 (m, 1H), 4.75 (d, J=5.6 Hz,2H), 4.51 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.41-3.35 (m, 1H), 2.56 (s,3H), 1.50 (d, J=6.8 Hz, 6H), 1.44 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.98minutes (Method C), m/z=408.1 [M+H]⁺.

Example 32:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(3-methyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.31 (dd, J=2.0, 7.6 Hz, 1H), 8.20 (dd, J=2.0,4.8 Hz, 1H), 7.03 (dd, J=4.8, 7.6 Hz, 1H), 6.97 (s, 1H), 5.56 (brs, 1H),4.78 (d, J=5.6 Hz, 2H), 4.49 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.43-3.36(m, 1H), 2.44 (s, 3H), 1.51 (d, J=6.8 Hz, 6H), 1.43 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=2.22 minutes (Method C), m/z=408.1 [M+H]⁺.

Example 33:3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from3-isopropyl-N-(4-methoxybenzyl)-1-methyl-6-(2-propoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amineand 1-methyl-1,2,4-triazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ=8.29 (dd, J=1.9, 7.4 Hz, 1H), 8.20 (dd, J=1.9,4.9 Hz, 1H), 8.05 (s, 1H), 7.02 (dd, J=5.0, 7.3 Hz, 1H), 6.97 (s, 1H),5.83 (brs, 1H), 4.61 (d, J=4.5 Hz, 2H), 4.39 (t, J=6.8 Hz, 2H), 4.05 (s,3H), 3.95 (s, 3H), 3.48-3.37 (m, 1H), 1.86 (sxt, J=7.2 Hz, 2H), 1.50 (d,J=7.0 Hz, 6H), 1.06 (t, J=7.4 Hz, 3H). LC-MS: t_(R)=1.98 minutes (MethodC), m/z=421.1 [M+H]⁺.

Example 34:3-isopropyl-1-methyl-N-[(1-methylimidazol-4-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from3-isopropyl-N-(4-methoxybenzyl)-1-methyl-6-(2-propoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amineand 1-methylimidazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ=8.29 (dd, J=1.9, 7.4 Hz, 1H), 8.19 (dd, J=1.9,4.9 Hz, 1H), 7.45 (s, 1H), 7.02 (dd, J=4.9, 7.4 Hz, 1H), 6.96 (s, 1H),6.85 (s, 1H), 5.51 (brs, 1H), 4.47 (d, J=5.0 Hz, 2H), 4.37 (t, J=6.8 Hz,2H), 4.04 (s, 3H), 3.69 (s, 3H), 3.34 (quin, J=6.8 Hz, 1H), 1.82 (sxt,J=7.2 Hz, 2H), 1.46 (d, J=6.8 Hz, 6H), 1.05 (t, J=7.4 Hz, 3H). LC-MS:t_(R)=1.7 minutes (Method C), m/z=420.1 [M+H]⁺.

Example 35:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(4-methylpyrimidin-2-yl)methanamine hydrochloride and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.65 (d, J=4.2 Hz, 1H), 8.30 (d, J=7.6 Hz,1H), 8.20 (d, J=4.2 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 7.05-7.01 (m, 1H),6.97 (s, 1H), 6.85 (brs, 1H), 4.71 (d, J=4.0 Hz, 2H), 4.51 (q, J=7.2 Hz,2H), 4.06 (s, 3H), 3.62-3.58 (m, 1H), 2.62 (s, 3H), 1.57 (d, J=6.0 Hz,6H), 1.47 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.19 minutes (Method C),m/z=418.1 [M+H]⁺.

Example 36:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,pyrimidin-2-ylmethanamine hydrochloride and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.82 (d, J=4.8 Hz, 2H), 8.31 (dd, J=2.0, 7.6Hz, 1H), 8.20 (dd, J=2.0, 7.6 Hz, 1H), 7.31 (t, J=4.8 Hz, 1H), 7.05 (dd,J=4.2, 7.6 Hz, 1H), 7.00 (s, 1H), 6.71 (brs, 1H), 4.78 (d, J=4.0 Hz,2H), 4.51 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.60-3.53 (m, 1H), 1.55 (d,J=6.8 Hz, 6H), 1.48 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=2.16 minutes (MethodC), m/z=404.1 [M+H]⁺.

Example 37:6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(6-methoxypyridin-3-yl)methanamine and (2-ethoxypyridin-3-yl)boronicacid

¹H NMR (CDCl₃ 400 MHz): δ 8.30 (dd, J=2.0, 7.6 Hz, 1H), 8.22 (d, J=2.0Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.63 (dd, J=2.4, 8.8 Hz, 1H),7.02 (dd, J=5.2, 7.4 Hz, 1H), 6.99 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.06(t, J=4.8 Hz, 1H), 4.51 (d, J=5.2 Hz, 2H), 4.44 (q, J=6.8 Hz, 2H), 4.05(s, 3H), 3.95 (s, 3H), 3.28-3.21 (m, 1H), 1.44 (d, J=7.2 Hz, 6H), 1.35(t, J=6.8 Hz, 3H). LC-MS: t_(R)=2.03 minutes (Method A), m/z=433.1[M+H]⁺.

Example 38:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(2-(trifluoromethyl)pyridin-3-yl)methanamine and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ=8.65 (d, J=4.8 Hz, 1H), 8.29 (dd, J=1.6, 7.6Hz, 1H), 8.16 (dd, J=2.0, 4.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.49 (dd,J=4.4, 8.0 Hz, 1H), 7.00 (dd, J=5.2, 7.6 Hz, 1H), 6.83 (s, 1H), 5.34 (t,J=6.0 Hz, 1H), 4.90 (d, J=6.0 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H), 4.07 (s,3H), 3.40-3.28 (m, 1H), 1.51 (d, J=6.4 Hz, 6H), 1.13 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=2.29 minutes (Method A), m/z=471 [M+H]⁺.

Example 39:6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(4-methoxypyridin-2-yl)methanamine and (2-ethoxypyridin-3-yl)boronicacid

¹H NMR (CDCl₃ 400 MHz): δ 8.46 (d, J=5.6 Hz, 1H), 8.30 (dd, J=2.0, 7.6Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.02 (dd, J=4.8, 7.2 Hz, 1H),6.91 (s, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.79 (d, J=3.2 Hz, 1H), 6.53 (brs,1H), 4.60 (d, J=4.4 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.86(s, 3H), 3.54-3.47 (s, 1H), 1.52 (d, J=6.8 Hz, 6H), 1.40 (t, J=7.2 Hz,3H). LC-MS: t_(R)=1.58 minutes (Method A), m/z=433.1 [M+H]⁺.

Example 40:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(2-pyridylmethyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand picolinaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.66-8.65 (m, 1H), 8.32-8.30 (m, 1H),8.20-8.18 (m, 1H), 7.74-7.70 (m, 1H), 7.36-7.34 (m, 1H), 7.29-7.25 (m,1H), 7.04-7.01 (m, 1H), 6.94 (s, 1H), 6.62 (brs, 1H), 4.67 (d, J=4.8 Hz,2H), 4.46 (q, J=6.8 Hz, 2H), 4.06 (s, 3H), 3.56-3.49 (m, 1H), 1.54 (d,J=6.8 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.84 minutes (MethodA), m/z=403.1 [M+H]⁺.

Example 41:6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand 6-methoxypicolinaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.32-8.31 (m, 1H), 8.20-8.19 (m, 1H),7.62-7.58 (m, 1H), 7.05-7.02 (m, 1H), 6.97 (s, 1H), 6.93-6.91 (m, 1H),6.72-6.70 (m, 1H), 6.33 (br.s, 1H), 4.60-4.58 (m, 2H), 4.48 (q, J=6.8Hz, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 3.53-3.49 (m, 1H), 1.51 (d, J=6.8Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.2 minutes (Method A),m/z=433.1 [M+H]⁺.

Example 42:6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dichloro-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(6-methylpyridin-2-yl)methanamine and (2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.32-8.30 (m, 1H), 8.20-8.19 (m, 1H), 7.62 (t,J=7.6 Hz, 1H), 7.15-7.12 (m, 2H), 7.05-7.02 (m, 1H), 6.93 (s, 1H), 6.90(br.s, 1H), 4.62-4.61 (m, 2H), 4.48 (q, J=6.8 Hz, 2H), 4.06 (s, 3H),3.61-3.58 (m, 1H), 2.63 (s, 3H), 1.56 (d, J=7.2 Hz, 6H), 1.43 (t, J=7.2Hz, 3H). LC-MS: t_(R)=1.8 minutes (Method A), m/z=417.1 [M+H]⁺.

Example 43:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine

Preparation of2-((2-chloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile

To a solution of2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine (430 mg, 1.76mmol) in NMP (5 mL) was added 2-aminoacetonitrile hydrochloride (326 mg,3.52 mmol) and triethylamine (535 mg, 5.28 mmol). The mixture was heatedat 120° C. for 16 hours. The mixture was cooled to 20° C. and ethylacetate (20 mL) was added. The organic layer was washed with H₂O (20mL×2), brine (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (0%˜30% ethylacetate in petroleum ether) to give2-((2-chloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile.

Preparation of2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile

To a solution of2-((2-chloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile(50 mg, 0.19 mmol) in dioxane (2 mL) was added(2-ethoxypyridin-3-yl)boronic acid (47 mg, 0.28 mmol), Cs₂CO₃ (124 mg,0.38 mmol) and[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12 mg,0.02 mol). The mixture was degassed with N₂ and heated at 80° C. for 2hours. The mixture was cooled to 20° C. and extracted with ethyl acetate(20 mL×2). The combined organic phases were washed with H₂O (20 mL),brine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The residue was purified by flash chromatography onsilica gel (10%˜50% ethyl acetate in petroleum ether) to give2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile.

Preparation of2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)-N′-hydroxyacetimidamide

To a solution of2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)acetonitrile(40 mg, 0.11 mmol) in EtOH (2 mL) was added NH₂OH.HCl (16 mg, 0.23 mmol)and diisopropylethylamine (30 mg, 0.23 mmol). The mixture was heated at90° C. for 16 hours. The mixture was concentrated and the residue wasdissolved in dichloromethane (20 mL) and NaHCO₃ (10 mL). The aqueouslayer was extracted with dichloromethane (20 mL). The combined organiclayers was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (10%˜100% ethyl acetatein petroleum ether) to give2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)-N-hydroxyacetimidamide.

Preparation ofN-((1,2,4-oxadiazol-3-yl)methyl)-2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amine

A solution of2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)amino)-N-hydroxyacetimidamide(50 mg, 0.13 mmol), triethoxymethane (2 mL, 12.01 mmol) and BF₃.Et₂O(0.1 mL, 0.8 mmol) was heated at 90° C. for 2 hours. The mixture wasconcentrated and the residue was dissolved in ethyl acetate (20 mL). Theorganic layer was washed with saturated aqueous NaHCO₃ solution (10 mL),H₂O (10 mL), brine (10 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (10%˜100% ethyl acetate in petroleum ether). Then the residue waspurified by SFC to giveN-((1,2,4-oxadiazol-3-yl)methyl)-2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amine.

¹H NMR (CDCl₃ 400 MHz): δ 8.78 (s, 1H), 8.23 (dd, J=2.0, 4.2 Hz, 1H),7.95 (dd, J=1.6, 7.6 Hz, 1H), 7.00 (dd, J=4.2, 7.6 Hz, 1H), 6.17 (s,1H), 5.65 (br. s, 1H), 4.71 (d, J=4.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H),3.38-3.32 (m, 1H), 2.70 (s, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.42 (t, J=6.8Hz, 3H). LC-MS: t_(R)=2.09 minutes (Method C), m/z=394 [M+H]⁺.

Example 44:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltriazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 26 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 4-(bromomethyl)-2-methyl-2H-1,2,3-triazole

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=4.8, 2.0 Hz, 1H), 8.04 (dd, J=7.6,2.0 Hz, 1H), 7.58 (s, 1H), 7.01 (dd, J=7.2, 4.8 Hz, 1H), 6.11 (s, 1H),5.49-5.47 (m, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H), 4.22(s, 3H), 3.33-3.26 (m, 1H), 2.70 (s, 3H), 1.46 (d, J=7.2 Hz, 6H), 1.38(t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.05 minutes (Method C), m/z=407.1[M+H]⁺.

Example 45:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(5-methyl-1,3,4-oxadiazol-2-yl)methanamine oxalate and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=4.8, 2.0 Hz, 1H), 8.03 (dd, J=7.2,2.0 Hz, 1H), 7.02-6.99 (m, 1H), 6.16 (s, 1H), 5.61-5.58 (m, 1H), 4.71(d, J=5.6 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 3.37-3.30 (m, 1H), 2.70 (s,3H), 2.57 (s, 3H), 1.47 (d, J=6.8 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=2.05 minutes (Method C), m/z=408 [M+H]⁺.

Example 46:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Preparation of ethyl2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)(4-methoxybenzyl)amino)acetate

To a solution of2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amine(50 mg, 0.12 mmol) in DMSO (2 mL) was added ethyl 2-bromoacetate (39 mg,0.23 mmol), Nal (35 mg, 0.23 mmol) and t-BuOK (39 mg, 0.35 mmol). Themixture was heated at 100° C. for 16 hours. The mixture was cooled to20° C. ethyl acetate (20 mL) and H₂O (10 mL) were added. The organiclayer was washed with H₂O (10 ml×2), brine (10 mL), dried over Na₂SO₄,filtered and concentrate. The crude was purified by preparative TLC(SiO₂, petroleum ether/ethyl acetate=2/1) to give ethyl2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)(4-methoxybenzyl)amino)acetate.

Preparation of ethyl2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methypimidazo[1,5-b]pyridazin-4-amine

Molecular sieves 4 Å (100 mg) were added to a solution of(Z)—N-hydroxyacetimidamide (17 mg, 0.23 mmol) in THF (3 mL). The mixturewas stirred at 20° C. for 30 minutes. Then NaH (9 mg, 0.23 mmol) (60% inmineral oil) was added and the mixture was heated at 50° C. for 30minutes. Then the mixture was cooled to 20° C. and a solution of ethyl2-((2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-yl)(4-methoxybenzyl)amino)acetate(40 mg, 0.08 mmol) in THF (2 mL) was added. The mixture was heated at80° C. for 2 hours. Water (1 mL) was added. The mixture was extractedwith ethyl acetate (20 mL×2). The combined organic phases were washedwith H₂O (50 mL), brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by preparative TLC (SiO₂,petroleum ether/ethyl acetate=2/1) to give2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)imidazo[1,5-b]pyridazin-4-amine.

Preparation of ethyl2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methypimidazo[1,5-b]pyridazin-4-amine

A solution of2-(2-ethoxypyridin-3-yl)-5-isopropyl-N-(4-methoxybenzyl)-7-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methypimidazo[1,5-b]pyridazin-4-amine(40 mg, 0.07 mmol) in TFA (5 mL) was heated at 60° C. for 16 hours. Themixture was concentrated. H₂O (2 mL) was added to the residue. Themixture was adjusted to pH=7 by sat.aq.NaHCO₃ and extracted with ethylacetate (10 mL×2). The combined organic phases were washed with H₂O (10mL), brine (10 mL), dried over Na₂SO₄, filtered and concentrated. Thecrude was purified by preparative TLC (SiO₂, petroleum ether/ethylacetate=1/1) to give2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)imidazo[1,5-b]pyridazin-4-amine.

¹H NMR (CDCl₃ 400 MHz): δ 8.24 (dd, J=2.0, 4.8 Hz, 1H), 7.61 (d, J=2.4,1H), 7.00 (dd, J=4.2, 7.6 Hz, 1H), 6.10 (s, 1H), 5.66-5.63 (m, 1H), 4.72(d, J=5.6 Hz, 2H), 4.47 (q, J=7.2 Hz, 2H), 3.40-3.33 (m, 1H), 2.72 (s,3H), 2.44 (s, 3H), 1.50 (d, J=7.2 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=1.97 minutes (Method C), m/z=408.1 [M+H]⁺.

Example 47:(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 1-methyl-1H-pyrazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 5.2 Hz, 1H), 8.06 (dd, J=2.0,7.2 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.00 (dd, J=5.6, 7.6 Hz, 1H),6.13 (s, 1H), 5.02-5.00 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.37 (d, J=4.8Hz, 2H), 3.93 (s, 3H), 2.86-2.80 (m, 1H), 2.70 (s, 3H), 1.92-1.87 (m,1H), 1.73-1.71 (m, 1H), 1.41-1.37 (m, 6H), 0.87 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=1.76 minutes (Method A), m/z=420.1 [M+H]⁺. [α]_(D) ²−5.6(c=0.4, MeOH)

Example 48:(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 1-methyl-1H-pyrazole-4-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 5.2 Hz, 1H), 8.06 (dd, J=2.0,7.2 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.00 (dd, J=4.8, 7.6 Hz, 1H),6.13 (s, 1H), 5.02-5.00 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.37 (d, J=4.8Hz, 2H), 3.93 (s, 3H), 2.86-2.80 (m, 1H), 2.70 (s, 3H), 1.92-1.89 (m,1H), 1.73-1.69 (m, 1H), 1.41-1.37 (m, 6H), 0.87 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=1.76 minutes (Method A), m/z=420.1 [M+H]⁺. [α]_(D) ²⁰+6.0(c=0.4, MeOH)

Example 49:(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 26 from(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 5.2 Hz, 1H), 8.07-8.05 (m,2H), 7.00 (dd, J=4.8, 7.2 Hz, 1H), 6.13 (s, 1H), 5.95 (brs, 1H), 4.56(d, J=4.4 Hz, 2H), 4.47 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 3.13-3.07 (m,1H), 2.71 (s, 3H), 1.98-1.93 (m, 1H), 1.79-1.75 (m, 1H), 1.48-1.42 (m,6H), 0.97 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.89 minutes (Method C),m/z=421.1 [M+H]⁺. [α]_(D) ²⁰−2.2 (c=0.5, CHCl₃)

Example 50:(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 26 from(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 5.2 Hz, 1H), 8.08-8.05 (m,2H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 6.13 (s, 1H), 5.95 (brs, 1H), 4.56(d, J=4.4 Hz, 2H), 4.47 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 3.13-3.07 (m,1H), 2.71 (s, 3H), 1.98-1.95 (m, 1H), 1.79-1.75 (m, 1H), 1.48-1.42 (m,6H), 0.97 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.89 minutes (Method C),m/z=421.1 [M+H]⁺. [α]_(D) ²⁰+4.6 (c=0.5, CHCl₃)

Example 51:(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 4.8 Hz, 1H), 8.05 (dd, J=2.0,7.6 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.00 (dd, J=4.8, 7.2 Hz, 1H), 6.35(d, J=2.4 Hz, 1H), 6.14 (s, 1H), 5.72 (brs, 1H), 4.56 (d, J=4.8 Hz, 2H),4.47 (q, J=7.2 Hz, 2H), 3.04-2.99 (m, 1H), 2.72 (s, 3H), 1.95-1.93 (m,1H), 1.77-1.72 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H),0.92 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.71 minutes (Method A), m/z=406.1[M+H]⁺. [α]_(D) ²⁰+3.3 (c=0.4, MeOH)

Example 52:(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 1H-pyrazole-3-carbaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 4.8 Hz, 1H), 8.05 (dd, J=2.0,7.6 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.00 (dd, J=4.8, 7.2 Hz, 1H), 6.35(d, J=2.4 Hz, 1H), 6.14 (s, 1H), 5.72 (brs, 1H), 4.56 (d, J=4.8 Hz, 2H),4.47 (q, J=7.2 Hz, 2H), 3.04-2.97 (m, 1H), 2.71 (s, 3H), 1.95-1.93 (m,1H), 1.77-1.72 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H),0.92 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.71 minutes (Method A), m/z=406.1[M+H]⁺. [α]_(D) ²⁰−3.4 (c=0.4, MeOH)

Example 53:(+)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 26 from(+)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 4-(chloromethyl)-2-methoxy-pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.20 (dd, J=2.0, 5.2 Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 8.02 (dd, J=2.0, 7.6 Hz, 1H), 6.97 (dd, J=5.2, 7.6 Hz, 1H),6.87 (dd, J=1.6, 5.2 Hz, 1H), 6.74 (d, J=1.6 Hz, 1H), 5.96 (s, 1H), 5.35(brt, J=6.0 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H),3.94 (s, 3H), 2.98-2.93 (m, 1H), 2.71 (s, 3H), 1.99-1.94 (m, 1H),1.80-1.76 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 0.94(t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.88 minutes (Method A), m/z=447.1[M+H]⁺. [α]_(D) ²⁰+4.0 (c=0.6, CHCl₃)

Example 54:(−)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 26 from(−)-5-(sec-butyl)-2-(2-ethoxypyridin-3-yl)-N-(4-methoxybenzyl)-7-methylimidazo[1,5-b]pyridazin-4-amineand 4-(chloromethyl)-2-methoxy-pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.20 (dd, J=2.0, 5.2 Hz, 1H), 8.16 (d, J=5.2Hz, 1H), 8.02 (dd, J=2.0, 7.6 Hz, 1H), 6.97 (dd, J=5.2, 7.6 Hz, 1H),6.87 (dd, J=1.6, 5.2 Hz, 1H), 6.74 (d, J=1.6 Hz, 1H), 5.96 (s, 1H), 5.35(brt, J=6.0 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H),3.94 (s, 3H), 3.00-2.91 (m, 1H), 2.71 (s, 3H), 2.01-1.94 (m, 1H),1.80-1.78 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 0.94(t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.88 minutes (Method A), m/z=447.1[M+H]⁺. [α]_(D) ²⁰−4.3 (c=0.6, CHCl₃)

Example 55:3-isopropyl-6-(2-methoxy-3-pyridyl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and(2-methoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.23-8.21 (m, 2H), 8.05 (s, 1H), 7.06-7.03 (m,1H), 6.87 (s, 1H), 5.83 (brs, 1H), 4.63 (d, J=4.8 Hz, 2H), 4.04 (s, 3H),4.04 (s, 3H), 3.95 (s, 3H), 3.46-3.39 (m, 1H). 1.50 (d, J=6.8 Hz, 6H).LC-MS: t_(R)=1.82 minutes (Method B), m/z=393.1 [M+H]⁺.

Example 56:3-(3-isopropyl-1-methyl-4-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-methylpyridin-2(1H)-one

6-Bromo-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine(prepared in a way similar to6-chloro-3-isopropyl-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-aminein example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine and(1-methyl-1H-1,2,4-triazol-3-yl)methanamine) (50 mg, 0.14 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,-2-dioxaborolane(70 mg, 0.28 mmol), 3-bromo-1-methyl-pyridin-2-one (52 mg, 0.28 mmol),Cs₂CO₃ (112 mg, 0.34 mmol) and Pd(dppf)Cl₂ (25 mg, 0.034 mmol) weretaken up into a microwave tube in dioxane (1 mL) and H₂O (0.25 mL). Thesealed tube was heated at 100° C. for 1 hour under microwave. Thereaction mixture was partitioned between ethyl acetate (20 mL) and H₂O(20 mL). The organic phase was separated, washed with H₂O (10 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flash silica gelchromatography (SiO₂, Dichloromethane: Methanol=1/0 to 10:1) andlyophilized to give3-[3-isopropyl-1-methyl-4-[(1-methyl-1,2,4-triazol-3-yl)methylamino]pyrazolo[3,4-b]pyridin-6-yl]-1-methyl-pyridin-2-one.

¹H NMR (CDCl₃ 400 MHz): δ 8.45 (dd, J=2.0, 6.8 Hz, 1H), 8.03 (s, 1H),7.59 (s, 1H), 7.41 (dd, J=2.0, 6.8 Hz, 1H), 6.36 (d, J=6.8, 6.8 Hz, 1H),5.80 (brs, 1H), 4.68 (d, J=4.8 Hz, 2H), 4.03 (s, 3H), 3.93 (s, 3H), 3.67(s, 3H), 3.44-3.36 (m, 1H), 1.48 (d, J=6.8 Hz, 6H). LC-MS: t_(R)=1.57minutes (Method B), m/z=393.1 [M+H]⁺.

Example 57:3-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine

To a solution of6-bromo-3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(100 mg, 0.27 mmol) in dioxane (2 mL) was added2-methoxy-3-(tributylstannyl)pyrazine (164 mg, 0.41 mmol), CsF (83 mg,0.55 mmol), Pd-PEPPSI precatalyst(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II))(11 mg, 0.01 mmol) and 4 Å molecular sieves (50 mg). The mixture wasdegassed with N₂ and heated at 100° C. for 16 hours. The mixture wasfiltered and the filter cake was washed with 10% MeOH in dichloromethane(20 mL). The filtrate was concentrated. The residue was purified byflash silica gel chromatography (SiO₂, 0˜10% MeOH/dichloromethane) togive the crude product. The crude product was purified by preparativeHPLC to give3-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine.

¹H NMR (CDCl₃ 400 MHz): δ 8.32 (d, J=2.4 Hz, 1H), 8.17 (d, J=2.8 Hz,1H), 8.04 (s, 1H), 6.78 (s, 1H), 5.92-5.90 (m, 1H), 4.62 (d, J=4.8 Hz,2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.94 (s, 3H), 3.46-3.40 (m, 1H), 1.50(d, J=6.8 Hz, 6H). LC-MS: t_(R)=1.59 minutes (Method B), m/z=394.1[M+H]⁺.

Example 58:3-isopropyl-1-methyl-6-(2-methyl-3-thienyl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and4,4,5,5-tetramethyl-2-(2-methylthiophen-3-yl)-1,3,2-dioxaborolane

¹H NMR (CDCl₃ 400 MHz): δ 8.04 (s, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.11 (d,J=5.2 Hz, 1H), 6.42 (s, 1H), 5.78 (brs, 1H), 4.61 (d, J=5.2 Hz, 2H),4.03 (s, 3H), 3.94 (s, 3H), 3.44-3.37 (m, 1H), 2.74 (s, 3H), 1.50 (d,J=6.8 Hz, 6H). LC-MS: t_(R)=2.14 minutes (Method B), m/z=382 [M+H]⁺.

Example 59:3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of6-bromo-3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(0.1 g, 0.27 mmol), 4-methyloxazole (46 mg, 0.55 mmol), XPHOS-Pd-G3((2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) (12 mg, 0.013 mmol), t-BuOK (92 mg, 0.82 mmol) in DMA(4 mL) was stirred at 100° C. for 12 hours under N₂. The mixture wasconcentrated under vacuum and the residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0, 0/1) to afford3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine.

¹H NMR (CDCl₃; 400 MHz): δ 8.05 (s, 1H), 7.54 (d, J=0.8 Hz, 1H), 7.08(s, 1H), 5.95 (brs, 1H), 4.68 (d, J=4.8 Hz, 2H), 4.09 (s, 3H), 3.95 (s,3H), 3.44-3.37 (m, 1H), 2.31 (d, J=0.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 6H).LC-MS: t_(R)=1.73 minutes (Method B), m/z=367.1 [M+H]⁺.

Example 60:3-isopropyl-1-methyl-6-(4-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 56 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and 2-bromo-4-methylthiazole

¹H NMR (CDCl₃ 400 MHz): δ 8.05 (s, 1H), 7.17 (s, 1H), 6.99 (d, J=0.8 Hz,1H), 5.90 (brt, J=4 Hz, 1H), 4.71 (d, J=4.4 Hz, 2H), 4.05 (s, 3H), 3.95(s, 3H), 3.42-3.39 (m, 1H), 2.56 (d, J=0.8 Hz, 3H), 1.49 (d, J=7.2 Hz,6H). LC-MS: t_(R)=2.34 minutes (Method C), m/z=383 [M+H]⁺.

Example 61:3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of6-bromo-3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine(50 mg, 0.14 mmol), 4-methylthiazole (41 mg, 0.41 mmol),dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (6.4 mg, 0.014mmol), 2,2-dimethylpropanoic acid (5.6 mg, 0.055 mmol), K₂CO₃ (57 mg,0.41 mmol) and Pd(OAc)₂ (1.5 mg, 0.007 mmol) in toluene (3 mL) wasdegassed with N₂ and stirred at 110° C. for 12 hours. The solution wasconcentrated under vacuum. The residue was purified by flash silica gelchromatography (SiO₂, 0˜10% MeOH/dichloromethane). Then the residue wasfurther purified by preparative HPLC to afford3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine.

¹H NMR (CDCl₃ 400 MHz): δ 8.71 (s, 1H), 8.04 (s, 1H), 6.51 (s, 1H),5.87-5.84 (brt, J=5.2 Hz, 1H), 4.63 (d, J=4.8 Hz, 2H), 4.02 (s, 3H),3.94 (s, 3H), 3.43-3.36 (m, 1H), 2.79 (s, 3H), 1.49 (d, J=6.8 Hz, 6H).LC-MS: t_(R)=1.88 minutes (Method C), m/z=383 [M+H]⁺.

Example 62:3-isopropyl-1-methyl-6-(5-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 57 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and5-methyl-2-(tributylstannyl)thiazole

¹H NMR (CDCl₃ 400 MHz): δ 8.04 (s, 1H), 7.57 (s, 1H), 7.13 (s, 1H),5.88-5.87 (m, 1H), 4.68 (d, J=4.8 Hz, 2H), 4.04 (s, 3H), 3.94 (s, 3H),3.43-3.36 (m, 1H), 2.54 (s, 3H), 1.48 (d, J=6.8 Hz, 6H). LC-MS:t_(R)=2.35 minutes (Method C), m/z=383 [M+H]⁺.

Example 63:3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-phenyl-pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and phenylboronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.08-8.04 (m, 3H), 7.51-7.40 (m, 3H), 6.69 (s,1H), 5.82-5.79 (m, 1H), 4.66 (d, J=5.2 Hz, 2H), 4.07 (s, 3H), 3.94 (s,3H), 3.45-3.38 (m, 1H), 1.50 (d, J=6.8 Hz, 6H). LC-MS: t_(R)=1.77minutes (Method C), m/z=362.1 [M+H]⁺.

Example 64:3-isopropyl-6-(4-methoxypyrimidin-5-yl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 56 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and5-bromo-4-methoxypyrimidine

¹H NMR (CDCl₃ 400 MHz): δ 9.08 (s, 1H), 8.82 (s, 1H), 8.05 (s, 1H), 6.81(s, 1H), 5.88-5.87 (m, 1H), 4.62 (d, J=5.2 Hz, 2H), 4.11 (s, 3H), 4.04(s, 3H), 3.95 (s, 3H), 3.45-3.38 (m, 1H), 1.50 (d, J=7.2 Hz, 6H). LC-MS:t_(R)=1.65 minutes (Method B), m/z=394 [M+H]⁺.

Example 65:3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-thienyl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 57 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine andtributyl(thiophen-2-yl)stannane

¹H NMR (CDCl₃ 400 MHz): δ 8.04 (s, 1H), 7.67-7.66 (m, 1H), 7.39-7.37 (m,1H), 7.13-7.11 (m, 1H), 6.65 (s, 1H), 5.79-5.77 (m, 1H), 4.64 (d, J=5.2Hz, 2H), 4.03 (s, 3H), 3.94 (s, 3H), 3.41-3.35 (m, 1H), 1.48 (d, J=6.8Hz, 6H). LC-MS: t_(R)=2.05 minutes (Method C), m/z=368 [M+H]⁺.

Example 66:6-(3-ethoxypyridazin-4-yl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 57 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and3-ethoxy-4-(tributylstannyl)pyridazine

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.8 Hz, 1H), 8.16 (d, J=4.8 Hz,1H), 8.05 (s, 1H), 7.15 (s, 1H), 5.92-5.90 (m, 1H), 4.75 (q, J=6.8 Hz,2H), 4.63 (d, J=4.4 Hz, 2H), 4.05 (s, 3H), 3.95 (s, 3H), 3.44-3.40 (m,1H), 1.55 (t, J=7.2 Hz, 3H), 1.50 (d, J=7.2 Hz, 6H) LC-MS: t_(R)=1.74minutes (Method B), m/z=408.1 [M+H]⁺.

Example 67:3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(3-propoxypyridazin-4-yl)pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 57 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and3-ethoxy-4-(tributylstannyl)pyridazine

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.8 Hz, 1H), 8.14 (d, J=4.8 Hz,1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.91 (br t, J=4.4 Hz, 1H), 4.65-4.61(m, 4H), 4.04 (s, 3H), 3.94 (s, 3H), 3.45-3.38 (m, 1H), 1.99-1.90 (m,2H), 1.49 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) LC-MS: t_(R)=1.88minutes (Method E), m/z=422.1 [M+H]⁺.

Example 68:6-(3-ethoxy-4-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine

Prepared in a way similar to example 19 from4,6-dibromo-3-isopropyl-1-methyl-1H-pyrazolo[3,4-b]pyridine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and3-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.42-8.35 (m, 2H), 8.05 (s, 1H), 7.91 (d,J=4.0 Hz, 1H), 6.97 (s, 1H), 5.87 (br t, J=4.8 Hz, 1H), 4.61 (d, J=4.8Hz, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.06 (s, 3H), 3.95 (s, 3H), 3.45-3.39(m, 1H), 1.52-1.46 (m, 9H) LC-MS: t_(R)=1.64 minutes (Method E),m/z=407.1 [M+H]⁺.

Example 69:2-(3-ethoxypyridazin-4-yl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 57 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(1-methyl-1H-pyrazol-4-yl)methanamine and3-ethoxy-4-(tributylstannyl)pyridazine

¹H NMR (CDCl₃ 400 MHz): δ 8.97 (d, J=4.8 Hz, 1H), 7.87 (d, J=4.8 Hz,1H), 7.55 (s, 1H), 7.43 (s, 1H), 6.18 (s, 1H), 5.14 (t, J=4.8 Hz, 1H),4.73 (q, J=6.8 Hz, 2H), 4.40 (d, J=4.8 Hz, 2H), 3.94 (s, 3H), 3.21-3.14(m, 1H), 2.71 (s, 3H), 1.47 (t, J=6.8 Hz, 3H), 1.44 (d, J=6.4 Hz, 6H)LC-MS: t_(R)=1.64 minutes (Method E), m/z=407.1 [M+H]⁺.

Example 70:2-(3-ethoxy-4-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(1-methyl-1H-pyrazol-4-yl)methanamine and3-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.41 (s, 1H), 8.36 (d, J=4.8 Hz, 1H), 7.64 (d,J=4.8 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.07 (s, 1H), 5.07 (brs, 1H),4.37 (d, J=5.2 Hz, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.93 (s, 3H), 3.21-3.14(m, 1H), 2.71 (s, 3H), 1.42 (d, J=6.8 Hz, 6H), 1.41 (t, J=6.8 Hz, 3H)LC-MS: t_(R)=1.49 minutes (Method E), m/z=406.1 [M+H]⁺.

Example 71:5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(1-methyl-1H-pyrazol-4-yl)methanamine and2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 5.2 Hz, 1H), 8.05 (dd, J=2.0,7.2 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.28 (dd, J=4.8, 7.2 Hz, 1H),6.12 (s, 1H), 4.99 (brs, 1H), 4.37 (d, J=6.4 Hz, 2H), 4.36 (t, J=7.2 Hz,2H), 3.93 (s, 3H), 3.20-3.14 (m, 1H), 2.70 (s, 3H), 1.84-1.75 (m, 2H),1.42 (d, J=6.8 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H) LC-MS: t_(R)=1.83 minutes(Method F), m/z=420.1 [M+H]⁺.

Example 72:5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

¹H NMR (CDCl₃ 400 MHz): δ 8.24 (dd, J=2.0, 4.8 Hz, 1H), 8.06-8.03 (m,2H), 7.02 (dd, J=4.8, 8.0 Hz, 1H), 6.11 (s, 1H), 5.94 (brs, 1H), 4.56(d, J=4.8 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.45-3.38 (m,1H), 2.72 (s, 3H), 1.88-1.79 (m, 2H), 1.50 (d, J=6.8 Hz, 6H), 1.07 (t,J=7.2 Hz, 3H) LC-MS: t_(R)=1.71 minutes (Method E), m/z=421.2 [M+H]⁺.

Example 73:2-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridypmethyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand 2-fluoronicotinaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.21-8.17 (m, 2H), 8.01-7.99 (m, 1H),7.99-7.78 (m, 1H), 7.21-7.19 (m, 1H), 6.99-6.95 (m, 1H), 6.10 (s, 1H),5.46 (br.s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.34 (q, J=6.8 Hz, 2H),3.36-3.30 (m, 1H), 2.74 (s, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.21 (t, J=6.8Hz, 3H). LC-MS: t_(R)=1.88 minutes (Method F), m/z=421 [M+H]⁺.

Example 74:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(2-pyridylmethyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 1 from2-(2-ethoxypyridin-3-yl)-5-isopropyl-7-methylimidazo[1,5-b]pyridazin-4-amineand nicotinaldehyde

¹H NMR (CDCl₃ 400 MHz): δ 8.65 (d, J=4.8 Hz, 1H), 8.27-8.25 (m, 1H),8.06-8.04 (m, 1H), 7.77-7.76 (m, 1H), 7.36-7.34 (m, 2H), 7.17 (br.s,1H), 7.04-7.01 (m, 1H), 6.23 (s, 1H), 4.61 (d, J=4.0 Hz, 2H), 4.48 (q,J=7.2 Hz, 2H), 3.68-361 (m, 1H), 2.84 (s, 3H), 1.58 (d, J=6.8 Hz, 6H),1.41 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.29 minutes (Method D), m/z=403[M+H]⁺.

Example 75:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(pyrimidin-2-ylmethyl)imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,pyrimidin-5-ylmethanamine hydrochloride and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.83 (d, J=5.2 Hz, 2H), 8.24 (dd, J=2.0, 5.2Hz, 1H), 8.07 (dd, J=2.0, 7.2 Hz, 1H), 7.34 (t, J=5.2 Hz, 1H), 7.03 (dd,J=5.2, 7.2 Hz, 1H), 6.84 (brs, 1H), 6.12 (s, 1H), 4.73 (d, J=4.0 Hz,2H), 4.52 (q, J=7.2 Hz, 2H), 3.62-3.55 (m, 1H), 2.72 (s, 3H), 1.54 (d,J=6.8 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.98 minutes (MethodE), m/z=404.1 [M+H]⁺.

Example 76:2-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(2-fluoropyrimidin-5-yl)methanamine hydrochloride and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.70 (s, 2H), 8.24 (dd, J=2.0, 5.2 Hz, 1H),8.07 (dd, J=2.0, 7.6 Hz, 1H), 7.03 (dd, J=5.2, 7.6 Hz, 1H), 6.62 (brs,1H), 6.11 (s, 1H), 4.73 (d, J=3.2 Hz, 2H), 4.51 (q, J=7.2 Hz, 2H),3.57-3.50 (m, 1H), 2.72 (s, 3H), 1.53 (d, J=7.2 Hz, 6H), 1.45 (t, J=7.2Hz, 3H). LC-MS: t_(R)=2.12 minutes (Method E), m/z=422 [M+H]⁺.

Example 77:2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(2-methoxypyridin-3-yl)methanamine and (2-ethoxypyridin-3-yl)boronicacid

¹H NMR (CDCl₃ 400 MHz): δ 8.21 (dd, J=2.0, 2.0 Hz, 1H), 8.13 (dd, J=1.6,1.6 Hz, 1H), 8.02 (dd, J=2.0, 2.0 Hz, 1H), 7.56 (dd, J=1.6, 1.6 Hz, 1H),7.00-6.97 (m, 1H), 6.91-6.89 (m, 1H), 6.04 (s, 1H), 5.55 (br.s, 1H),4.50 (d, J=5.6 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 4.03 (s, 3H), 3.34-3.27(m, 1H), 2.69 (s, 3H), 1.47 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=1.96 minutes (Method F), m/z=433.1 [M+H]⁺.

Example 78:2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,imidazo[1,5-a]pyridin-5-ylmethanamine and (2-ethoxypyridin-3-yl)boronicacid

¹H NMR (CDCl₃ 400 MHz): δ 8.19 (d, J=2.0 Hz, J=2.0 Hz 1H), 8.15 (s, 1H),8.06 (dd, J=1.6 Hz, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=9.2 Hz, 1H),6.99-6.96 (m, 1H), 6.80-6.78 (m, 1H), 6.70 (d, J=6.4 Hz, 1H), 6.13 (s,1H), 5.38 (br. s, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.28 (q, J=7.2 Hz, 2H),3.29-3.26 (m, 1H), 2.76 (s, 3H), 1.47 (d, J=6.8 Hz, 6H), 1.08 (t, J=6.8Hz, 3H). LC-MS: t_(R)=1.35 minutes (Method F), m/z=442.1 [M+H]⁺.

Example 79:2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,imidazo[1,2-a]pyridin-5-ylmethanamine and (2-ethoxypyridin-3-yl)boronicacid

¹H NMR (CDCl₃ 400 MHz): δ 8.19 (dd, J=4.8, 1.6 Hz, 1H), 8.06 (dd, J=7.6,2.0 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.61 (s, 1H),7.29-7.25 (m, 1H), 6.98 (dd, J=7.6, 4.8 Hz, 1H), 6.94 (d, J=6.8 Hz, 1H),6.14 (s, 1H), 5.41 (br s, 1H), 4.80 (d, J=5.6 Hz, 2H), 4.27 (q, J=7.2Hz, 2H), 3.31-3.24 (m, 1H), 2.75 (s, 3H), 1.47 (d, J=6.8 Hz, 6H), 1.06(t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.27 minutes (Method F), m/z=442.1[M+H]⁺.

Example 80:2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 19 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(2-(trifluoromethyl)pyridin-3-yl)methanamine and(2-ethoxypyridin-3-yl)boronic acid

¹H NMR (CDCl₃ 400 MHz): δ 8.65 (d, J=4.4 Hz, 1H), 8.19 (dd, J=1.6, 4.8Hz, 1H), 8.02 (dd, J=1.6, 7.2 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.52 (dd,J=4.4, 7.6 Hz, 1H), 6.97 (dd, J=4.8, 7.2 Hz, 1H), 5.95 (s, 1H), 5.45(brt, J=5.6 Hz, 1H), 4.86 (d, J=5.6 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H),3.36-3.26 (m, 1H), 2.71 (s, 3H), 1.49 (d, J=6.8 Hz, 6H), 1.13 (t, J=7.2Hz, 3H). LC-MS: t_(R)=1.8 minutes (Method F), m/z=471.1 [M+H]⁺.

Example 81:2-(1,3-benzoxazol-7-yl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine

Prepared in a way similar to example 56 from2,4-dichloro-5-isopropyl-7-methylimidazo[1,5-b]pyridazine,(1-methyl-1H-1,2,4-triazol-3-yl)methanamine and 7-bromobenzo[d]oxazole

¹H NMR (CDCl₃ 400 MHz) δ 8.23 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.07 (s,1H), 7.88 (d, J=7.2 Hz, 1H), 7.53-7.49 (m, 1H), 6.33 (s, 1H), 6.05 (brs, 1H), 4.68 (d, J=4.8 Hz, 2H), 3.96 (s, 3H), 3.48-3.36 (m, 1H), 2.76(s, 3H), 1.50 (d, J=6.8 Hz, 6H). LC-MS: t_(R)=1.68 minutes (Method E),m/z=403.1 [M+H]⁺.

In Vitro Testing

PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wereperformed in 60 μL samples containing a fixed amount of the PDE1 enzyme(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA (bovine serumalbumin), 15 nM tritium labelled cAMP and varying amounts of inhibitors.Reactions were initiated by addition of the cyclic nucleotide substrate,and reactions were allowed to proceed for 1 hr at room temperaturebefore being terminated through mixing with 20 μL (0.2 mg) yttriumsilicate SPA beads (PerkinElmer). The beads were allowed to settle for 1hr in the dark before the plates were counted in a Wallac 1450 Microbetacounter. The measured signals were converted to activity relative to anuninhibited control (100%) and IC₅₀ values were calculated using XIFit(model 205, IDBS).

The invention claimed is:
 1. A compound of formula (I)

wherein Y₁=N—R₁, Y₂=C and Y₃=C, or Y₁=C—R₁, Y₂=N and Y₃=C; Z₁ isselected from NH, CH₂, O and S; Z₂ is selected from NH, CH₂, O and S;with the proviso that at least one of Z₁ and Z₂ is CH₂; R₁ is selectedfrom the group consisting of hydrogen, linear or branched C₁₋₄ alkyl andsaturated monocyclic C₃₋₄ cycloalkyl, wherein said linear or branchedC₁₋₄ alkyl and saturated monocyclic C₃₋₄ cycloalkyl can be optionallysubstituted with one or more halogen; R₂ is selected from the groupconsisting of linear or branched C₁₋₆ alkyl, saturated monocyclic C₃₋₆cycloalkyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, all ofwhich can optionally be substituted with one or more halogen; R₃ is a 5-or 6-membered heteroaryl, which can optionally be substituted with oneor more substituents selected from linear or branched C₁₋₄ alkyl, linearor branched C₁₋₄ alkoxy and halogen, wherein said linear or branchedC₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be optionallysubstituted with one or more halogen, or R₃ is a 9-membered bicyclicheteroaryl, which can optionally be substituted with one or moresubstituents selected from linear or branched C₁₋₄ alkyl, linear orbranched C₁₋₄ alkoxy and halogen, wherein said linear or branched C₁₋₄alkyl and linear or branched C₁₋₄ alkoxy can be optionally substitutedwith one or more halogen; R₄ is a 5- or 6-membered heteroaryl, which canoptionally be substituted with one or more substituents selected fromlinear or branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy andhalogen, wherein said linear or branched C₁₋₄ alkyl and linear orbranched C₁₋₄ alkoxy can be optionally substituted with one or morehalogen, or R₄ is a phenyl, which can optionally be substituted with oneor more substituents selected from linear or branched C₁₋₄ alkyl, linearor branched C₁₋₄ alkoxy and halogen, wherein said linear or branchedC₁₋₄ alkyl and linear or branched C₁₋₄ alkoxy can be optionallysubstituted with one or more halogen, or R₄ is a pyridinone, which canoptionally be substituted with one or more substituents selected fromlinear or branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy andhalogen, wherein said linear or branched C₁₋₄ alkyl and linear orbranched C₁₋₄ alkoxy can be optionally substituted with one or morehalogen; or R₄ is a 9-membered bicyclic heteroaryl, which can optionallybe substituted with one or more substituents selected from linear orbranched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy and halogen, whereinsaid linear or branched C₁₋₄ alkyl and linear or branched C₁₋₄ alkoxycan be optionally substituted with one or more halogen; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 of formula (Ia)

wherein Z₁, Z₂, R₁, R₂, R₃ and R₄ are as defined in claim 1; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 of formula (Ib)

wherein Z₁, Z₂, R₁, R₂, R₃ and R₄ are as defined in claim 1; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1, wherein Z₁ is NH.
 5. The compound according to claim 1, whereinZ₂ is CH₂.
 6. The compound according to claim 1, wherein Z₁ is NH and Z₂is CH₂.
 7. The compound according to claim 1, wherein R₁ is a linear orbranched C₁₋₄ alkyl.
 8. The compound according to claim 1, wherein R₂ islinear or branched C₁₋₆ alkyl.
 9. The compound according to claim 1,wherein R₃ is a 5-membered heteroaryl selected from pyrazolyl,imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl andthiophenyl, all of which can optionally be substituted with a methyl; orR₃ is a 6-membered heteroaryl, which can optionally be substituted witha substituent selected from methyl, trifluoromethyl or a linear orbranched C₁₋₄ alkoxy; wherein said 6-membered heteroaryl is selectedfrom pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; or R₃ is a9-membered bicyclic heteroaryl, which is optionally substituted with oneor more methyl.
 10. The compound according to claim 1, wherein R₄ is a5-membered heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and thiophenyl whereinsaid 5-membered heteroaryl can be optionally substituted with a methyl;or R₄ is a 6-membered heteroaryl, which can optionally be substitutedwith a linear or branched C₁₋₄ alkoxy; wherein said 6-memberedheteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl; or R₄ is a phenyl, which can optionally be substituted withone or more methyl; or R₄ is a pyridinone, which can optionally besubstituted with one or more methyl; or R₄ is a 9-membered bicyclicheteroaryl, which can optionally be substituted with one or more methyl.11. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of: 2)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;3)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1H-pyrazol-3-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;4)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;5)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;6)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;7)6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(2-ethoxy-4-pyridyl)methyl]-1-methylpyrazolo[3,4-b]pyridin-4-amine; 8)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylimidazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;9)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;10)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-3-ylmethyl)imidazo[1,5-b]pyrazin-4-amine;11)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;12)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;13)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;14)2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;15)2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;16)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;17)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methylthiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;18)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-4-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;19)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;20)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;21)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;22)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;23)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltetrazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;24)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;25)6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;26)6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)1H-pyrazolo[3,4-b]pyridin-4-amine; 27)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;28)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;29)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;30)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;31)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1l-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;32)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;33)3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;34)3-isopropyl-1-methyl-N-[(1-methylimidazol-4-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;35)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;36)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;37)6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;38)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[[2-(trifluoromethyl)-pyridyl]methyl]pyrazolo[3,4-b]pyridin-4-amine;39)6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;40)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(2-pyridylmethyl)pyrazolo[3,4-b]pyridin-4-amine;41)6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;42)6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[3,4-b]pyridin-4-amine;43)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;44)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltriazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;45)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;46)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;47)(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;48)(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;49)(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;50)(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;51)(+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;52)(−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;53)(+)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;54)(−)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;55)3-isopropyl-6-(2-methoxy-3-pyridyl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;56)3-(3-isopropyl-1-methyl-4-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-methylpyridin-2(1H)-one;57)3-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine;58)3-isopropyl-1-methyl-6-(2-methyl-3-thienyl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;59)3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine;60)3-isopropyl-1-methyl-6-(4-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;61)3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine;62)3-isopropyl-1-methyl-6-(5-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;63)3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]phenyl-pyrazolo[3,4-b]pyridin-4-amine;64)3-isopropyl-6-(4-methoxypyrimidin-5-yl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;65)3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-thienyl)pyrazolo[3,4-b]pyridin-4-amine;66)6-(3-ethoxypyridazin-4-yl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;67)3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(3-propoxypyridazin-4-yl)pyrazolo[3,4-b]pyridin-4-amine;68)6-(3-ethoxy-4-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;69)2-(3-ethoxypyridazin-4-yl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;70)2-(3-ethoxy-4-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;71)5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;72)5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;73)2-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;74)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(2-pyridylmethyl)imidazo[1,5-b]pyridazin-4-amine;75)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(pyrimidin-2-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;76)2-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;77)2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;78)2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;79)2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;80)2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,5-b]pyridazin-4-amine;81)2-(1,3-benzoxazol-7-yl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;and pharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers, diluents and/or excipients.13. The compound according to claim 2, wherein Z₁ is NH.
 14. Thecompound according to claim 2, wherein Z₂ is CH₂.
 15. The compoundaccording to claim 2, wherein R₁ is a linear or branched C₁₋₄ alkyl. 16.The compound according to claim 2, wherein R₂ is a linear or branchedC₁₋₄ alkyl.
 17. The compound according to claim 3, wherein Z₁ is NH. 18.The compound according to claim 3, wherein Z₂ is CH₂.
 19. The compoundaccording to claim 3, wherein R₁ is a linear or branched C₁₋₄ alkyl. 20.The compound according to claim 3, wherein R₂ is a linear or branchedC₁₋₄ alkyl.
 21. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 11, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers, diluents and/or excipients.